Oxaliplatin

Intrastrand and Interstrand DNA Crosslinks

This compound forms different types of DNA crosslinks. The most prevalent are intrastrand crosslinks, which occur between two adjacent purine bases on the same DNA strand, predominantly between two guanine residues (GG) or, less frequently, between guanine and adenine (GA). aacrjournals.orgscirp.orgnih.govnih.gov this compound also forms interstrand crosslinks, which are covalent bonds between bases on opposite DNA strands, and DNA-protein crosslinks. aacrjournals.orgnih.govoup.com While interstrand crosslinks are considered highly toxic DNA lesions, they constitute a smaller fraction of the total adducts formed by this compound compared to intrastrand crosslinks. aacrjournals.orgscirp.orgnih.gov

Specific DNA Binding Sites (e.g., N7-Guanine)

The reactive platinum species of this compound primarily binds to the N7 position of guanine residues in DNA. patsnap.comscirp.orgnih.govnih.gov Binding to adenine bases at the N7 position also occurs, though less frequently than with guanine. patsnap.comscirp.orgmetu.edu.tr This binding forms monoadducts, which can then react further with an adjacent purine base to form the more stable and cytotoxic diadducts, resulting in intrastrand or interstrand crosslinks. nih.govnih.govresearchgate.net

Inhibition of DNA Replication and Transcription

The formation of platinum-DNA adducts, particularly the intrastrand and interstrand crosslinks, causes distortions in the DNA helix. scirp.org These structural alterations act as physical blocks, preventing the enzymes involved in DNA replication (DNA polymerases) and transcription (RNA polymerases) from moving along the DNA template. wikipedia.orgpatsnap.commedchemexpress.comaacrjournals.orgscirp.orgmdpi.com This inhibition of DNA replication and transcription is a key mechanism by which this compound hinders cell division and protein synthesis, ultimately leading to cell cycle arrest and cell death. patsnap.commedchemexpress.comscirp.org

Activation of Homologous Recombination Repair Pathways

The DNA damage induced by this compound, including DNA crosslinks and double-strand breaks, activates cellular DNA damage response pathways. patsnap.comamegroups.org One of the key repair mechanisms involved in addressing this compound-induced DNA damage, particularly interstrand crosslinks and double-strand breaks, is homologous recombination (HR) repair. patsnap.comoup.comamegroups.orgnih.govdovepress.com HR is a major pathway for repairing double-strand breaks and is crucial for maintaining genomic integrity. amegroups.orgdovepress.com Activation of HR can contribute to resistance to this compound in cancer cells. nih.gov

Apoptosis Induction Mechanisms

This compound-induced DNA damage triggers signaling cascades that lead to the induction of apoptosis, a form of programmed cell death essential for eliminating damaged or unwanted cells. patsnap.commedchemexpress.comscirp.org Several mechanisms contribute to this compound-induced apoptosis. One important pathway involves the activation of the tumor suppressor protein p53, which can regulate the cell cycle and promote apoptosis in response to DNA damage. patsnap.commdpi.comnih.govmedwinpublishers.com this compound treatment has been shown to upregulate p53 in some cancer cell lines. medwinpublishers.com Additionally, this compound can activate the mitochondria-mediated apoptotic pathway, characterized by the release of cytochrome c from the mitochondria into the cytosol. patsnap.comnih.govnih.gov This release subsequently activates caspases, a family of proteases that execute the final stages of apoptosis, including caspase-3. patsnap.comnih.govnih.gov Studies have shown that this compound treatment results in caspase-3 activation. nih.gov The balance between pro-apoptotic and anti-apoptotic proteins, such as those in the Bcl-2 family, plays a critical role in regulating this compound-induced apoptosis. mdpi.comnih.govmedwinpublishers.com this compound may also induce apoptosis through mechanisms involving oxidative stress and the generation of reactive oxygen species (ROS). patsnap.commdpi.comijbs.com Increased ROS levels can cause further cellular damage and contribute to apoptosis. patsnap.comijbs.com Activation of signaling pathways like the p38 MAPK pathway has also been implicated as a key proapoptotic mediator of this compound-induced cell death in some cell lines. ijbs.comaacrjournals.org

Intrinsic Apoptotic Pathway Activation

The intrinsic apoptotic pathway, also known as the mitochondrial pathway, is a major route through which this compound exerts its cytotoxic effects. nih.govdiva-portal.org This pathway is initiated by intracellular stress signals, such as DNA damage induced by this compound, which converge on the mitochondria. spandidos-publications.com

This compound treatment can lead to mitochondrial dysfunction and derangement. nih.govresearchgate.net A key event in the activation of the intrinsic pathway is the mitochondrial outer membrane permeabilization (MOMP), which results in the release of pro-apoptotic factors from the intermembrane space into the cytosol. spandidos-publications.comjci.org Cytochrome C is a crucial protein released from the mitochondria during this process. nih.govspandidos-publications.comresearchgate.netunimib.itmdpi.com Once in the cytosol, cytochrome C binds with Apaf-1 and procaspase-9 to form the apoptosome, a molecular complex that activates caspase-9. jci.orgmdpi.com Activated caspase-9 subsequently cleaves and activates downstream effector caspases, such as caspase-3, leading to the execution of apoptosis. diva-portal.orgjci.orgmdpi.com Studies have shown that this compound can induce the cytosolic release of cytochrome C. nih.govresearchgate.net

The intrinsic apoptotic pathway is tightly regulated by the balance between pro-apoptotic and anti-apoptotic proteins, particularly those belonging to the Bcl-2 family. spandidos-publications.comnih.gov Anti-apoptotic proteins like Bcl-2 are typically localized on the outer mitochondrial membrane and prevent MOMP and the release of cytochrome C. spandidos-publications.comnih.gov this compound can influence the expression and activity of these proteins. Some research indicates that this compound treatment can lead to decreased expression of anti-apoptotic protein Bcl-2, thereby promoting the release of cytochrome C and activating the intrinsic pathway. nih.govoncotarget.comspandidos-publications.com Conversely, overexpression of anti-apoptotic Bcl-2 family members has been associated with resistance to chemotherapy, including this compound. oncotarget.com Bcl-2 interacts with various proteins, including pro-apoptotic members like Bax and Bak, and its binding to Bax can block the release of cytochrome C. mdpi.comnih.govmdpi.com

Extrinsic Apoptotic Pathway Activation

The extrinsic apoptotic pathway is initiated by the binding of extracellular death ligands to specific death receptors on the cell surface, leading to the formation of the death-inducing signaling complex (DISC). spandidos-publications.comjci.org While the intrinsic pathway is considered a primary mechanism for this compound-induced apoptosis, the extrinsic pathway also contributes to its cytotoxic effects in certain cell types. nih.govwjgnet.com

Activation of the extrinsic pathway involves the recruitment and activation of initiator caspases, particularly caspase-8, within the DISC. spandidos-publications.comjci.orgiiarjournals.org Activated caspase-8 can directly cleave and activate effector caspases or cleave the pro-apoptotic Bcl-2 family protein Bid. spandidos-publications.comjci.org Cleavage of Bid generates a truncated form (tBid) which translocates to the mitochondria and promotes MOMP, thereby linking the extrinsic and intrinsic pathways and amplifying the apoptotic signal. spandidos-publications.comjci.orgresearchgate.netplos.org Studies have shown that this compound can increase caspase-8 activity and Bid expression in certain cancer cell lines, indicating activation of the extrinsic pathway. nih.govwjgnet.com

The extrinsic pathway is initiated by the engagement of death receptors, such as Death Receptor 4 (DR4) and Death Receptor 5 (DR5), by their respective ligands (e.g., TRAIL). spandidos-publications.comjci.org While this compound's primary action is intracellular DNA damage, there is evidence suggesting its influence on death receptors. Some studies indicate that this compound, particularly in combination with other agents, can lead to increased expression or altered localization of death receptors like FasL and DR4, contributing to the activation of the extrinsic pathway. wjgnet.comiiarjournals.org The clustering of these receptors upon ligand binding is crucial for the formation of the DISC and subsequent caspase activation. jci.org

The induction of apoptosis by this compound is a multi-faceted process initiated by DNA damage. patsnap.com This damage serves as a signal that converges on the cellular apoptotic machinery, activating distinct yet interconnected pathways that culminate in controlled cell dismantling. nih.govspandidos-publications.com

Intrinsic Apoptotic Pathway Activation

The intrinsic apoptotic pathway, often referred to as the mitochondrial pathway, represents a significant route through which this compound mediates cell death. nih.govdiva-portal.org This pathway is triggered by intracellular stressors, including the DNA lesions induced by this compound, which impact mitochondrial integrity and function. spandidos-publications.com

A pivotal event in the activation of the intrinsic pathway is the permeabilization of the mitochondrial outer membrane (MOMP). spandidos-publications.comjci.org this compound can induce mitochondrial dysfunction, leading to MOMP and the subsequent release of pro-apoptotic factors from the mitochondrial intermembrane space into the cytosol. nih.govspandidos-publications.comresearchgate.netunimib.itmdpi.com Among these factors, Cytochrome C plays a critical role. nih.govspandidos-publications.comresearchgate.netunimib.itmdpi.com Upon its release into the cytosol, Cytochrome C interacts with Apaf-1 and procaspase-9, facilitating the formation of the apoptosome. jci.orgmdpi.com This complex serves as a platform for the autoactivation of caspase-9, an initiator caspase. jci.orgmdpi.com Activated caspase-9 then cleaves and activates executioner caspases, notably caspase-3, which are responsible for dismantling the cell. diva-portal.orgjci.orgmdpi.com Research indicates that this compound treatment can lead to the cytosolic translocation of Cytochrome C. nih.govresearchgate.net

The intrinsic apoptotic pathway is under stringent control by the balance between pro-apoptotic and anti-apoptotic proteins, particularly members of the Bcl-2 protein family. spandidos-publications.comnih.gov Anti-apoptotic proteins like Bcl-2 reside on the outer mitochondrial membrane and function to prevent MOMP and the release of pro-apoptotic factors like Cytochrome C. spandidos-publications.comnih.gov this compound can modulate the expression and activity of these regulatory proteins. Studies have demonstrated that this compound treatment can result in a decrease in the expression levels of the anti-apoptotic protein Bcl-2, thereby favoring the release of Cytochrome C and the activation of the intrinsic pathway. nih.govoncotarget.comspandidos-publications.com Conversely, the overexpression of anti-apoptotic Bcl-2 family proteins has been linked to reduced sensitivity and resistance to various chemotherapeutic agents, including this compound. oncotarget.com Bcl-2 interacts with numerous proteins, including pro-apoptotic counterparts such as Bax and Bak, and its binding to Bax is known to inhibit the release of Cytochrome C from mitochondria. mdpi.comnih.govmdpi.com

Mitochondrial Derangement and Cytochrome C Release

Extrinsic Apoptotic Pathway Activation

The extrinsic apoptotic pathway is triggered by the engagement of death receptors on the cell surface by their specific ligands, leading to the assembly of the death-inducing signaling complex (DISC). spandidos-publications.comjci.org While the intrinsic pathway is a major contributor to this compound-induced apoptosis, the extrinsic pathway also plays a role in mediating cell death in response to this drug in certain cellular contexts. nih.govwjgnet.com

Activation of the extrinsic pathway involves the recruitment and activation of initiator caspases, primarily caspase-8, within the DISC. spandidos-publications.comjci.orgiiarjournals.org Activated caspase-8 can directly activate executioner caspases or cleave the pro-apoptotic Bcl-2 family member Bid. spandidos-publications.comjci.org The cleavage of Bid generates a truncated form, tBid, which then translocates to the mitochondria. spandidos-publications.comjci.orgresearchgate.netplos.org tBid promotes MOMP, thereby establishing a link between the extrinsic and intrinsic pathways and amplifying the apoptotic signal. spandidos-publications.comjci.orgresearchgate.netplos.org Research indicates that this compound can enhance caspase-8 activity and increase Bid expression in certain cancer cell lines, suggesting the involvement of the extrinsic pathway. nih.govwjgnet.com

The extrinsic pathway is initiated by the interaction of death ligands (e.g., TRAIL) with their cognate death receptors, such as Death Receptor 4 (DR4) and Death Receptor 5 (DR5), on the cell membrane. spandidos-publications.comjci.org Although this compound's primary mechanism involves intracellular DNA damage, there is evidence suggesting its influence on death receptors. Some studies indicate that this compound, particularly when used in combination with other agents, can lead to the upregulation or altered localization of death receptors like FasL and DR4, contributing to the activation of the extrinsic apoptotic cascade. wjgnet.comiiarjournals.org The clustering of these receptors upon ligand binding is essential for the formation of the DISC and the subsequent activation of caspases. jci.org

Caspase-8 Activity and Bid Expression

Autophagy-Associated Apoptosis

Autophagy is a cellular process involving the degradation and recycling of damaged organelles and proteins. nih.gov While often acting as a survival mechanism in response to cellular stress, autophagy can also contribute to cell death or be intricately linked with apoptosis. nih.govmdpi.com Studies investigating the role of autophagy in this compound-treated cancer cells have yielded complex results, suggesting a context-dependent function.

In some instances, this compound treatment has been shown to induce autophagy in cancer cells. nih.gov This induction can be a protective response, helping cells cope with the stress imposed by the drug, and its inhibition may enhance this compound's cytotoxic effects. nih.govnih.govresearchgate.net For example, in Caco-2 colorectal cancer cells, this compound treatment increased the ratio of MAP1LC3B-II to Actin, a marker of autophagy, and inhibiting autophagy with pharmacological agents or siRNA targeting essential autophagy genes like ATG5 and Beclin1 potentiated this compound-induced cell death. nih.gov This suggests that in these cells, autophagy acts as a pro-survival mechanism against this compound. nih.gov

Conversely, other research indicates that this compound may reduce the expression of autophagy-related proteins like Atg5, beclin-1, Atg7, LC3-I, and LC3-II in a dose-dependent manner in certain cell lines, suggesting a potential inhibition of autophagy. nih.gov The interplay between this compound, autophagy, and apoptosis is a critical area of research, particularly in understanding mechanisms of drug resistance. mdpi.comresearchgate.net Autophagy-associated apoptosis, where autophagy directly contributes to cell death, has also been implicated as a mechanism facilitated by this compound in certain contexts. mdpi.com

Cell Cycle Perturbation and Arrest

The cell cycle is a tightly regulated series of events that leads to cell division. Anticancer agents often target specific phases of the cell cycle to inhibit cancer cell proliferation. This compound has been shown to induce cell cycle perturbation and arrest in various cancer cell lines. nih.govaacrjournals.org

A primary effect of this compound is the induction of G2/M cell cycle arrest, although a transient S phase delay has also been observed. nih.gov Studies using flow cytometry have demonstrated that this compound treatment leads to an accumulation of cells in the G2/M phase. nih.govaacrjournals.org For instance, in HT29, MCF7, Hela, and A549 cell lines, this compound treatment resulted in significant cell cycle modifications, with a prominent G2/M arrest. nih.gov The extent and reversibility of this arrest can vary depending on the cell line and treatment duration. nih.gov

Research has also explored the impact of this compound on cell cycle regulatory proteins. While not explicitly detailed in the provided snippets for this compound alone, studies involving combinations with this compound have shown alterations in the levels of cyclins A and B, as well as cdc2 and cdk2, which are key regulators of G2/M progression. tandfonline.com The induction of cell cycle arrest by this compound is considered a crucial mechanism contributing to its cytotoxic effects, preventing cancer cells from dividing and proliferating. researchgate.netmdpi.com

Reactive Oxygen Species Generation and Oxidative Stress Response

This compound treatment can lead to the generation of reactive oxygen species (ROS), which are highly reactive molecules that can cause oxidative stress and damage to cellular components, including DNA, lipids, and proteins. nih.govnih.govijbs.com Oxidative stress is recognized as an important factor in the toxicity of this compound, including mitochondrial toxicity. nih.gov

Studies have shown that this compound increases intracellular ROS levels in cancer cells. nih.govijbs.com This increased ROS production can contribute to this compound-induced DNA damage and apoptosis. nih.gov For example, in colorectal cancer cells, this compound treatment statistically significantly increased ROS levels. nih.gov The generation of ROS by this compound is considered a critical event in platinum-induced cell death. plos.org

The cellular response to this compound-induced oxidative stress involves various antioxidant defense mechanisms. However, excessive ROS generation can overwhelm these defenses, leading to cellular damage and the activation of cell death pathways. nih.govijbs.com The relationship between ROS, autophagy, and apoptosis in the context of this compound treatment is complex, with ROS potentially triggering autophagy and endoplasmic reticulum (ER) stress, which can in turn influence cell fate. nih.govplos.org

Immunogenic Cell Death Pathways

Immunogenic cell death (ICD) is a mode of cell death that elicits an adaptive immune response against dead-cell-associated antigens. This process involves the release of damage-associated molecular patterns (DAMPs) that can activate dendritic cells and prime T cell responses against cancer cells. researchgate.nettargetedonc.com this compound has been identified as an inducer of ICD. researchgate.nettargetedonc.comwjon.org

Compared to other platinum compounds like cisplatin and irinotecan, this compound has shown a greater capacity to induce ICD. targetedonc.comwjon.org This involves the translocation of calreticulin and other chaperones from the endoplasmic reticulum to the cell membrane, as well as the release of molecules like ATP and HMGB1. researchgate.net These events act as "eat-me" and "danger" signals, promoting the uptake of tumor antigens by dendritic cells and subsequent activation of cytotoxic T lymphocytes. researchgate.netresearchgate.net

Research suggests that the immunogenic properties of this compound contribute to its therapeutic efficacy, particularly in colorectal cancer. targetedonc.comwjon.org The activation of the host immune system by this compound-induced ICD can enhance the antitumor effect. researchgate.net Studies have explored the association between genetic variations in ICD pathways and the efficacy of this compound-based chemotherapy. targetedonc.com The cGAS-STING signaling pathway has also been implicated in this compound-induced ICD in certain cancer types. biorxiv.org

Nucleolar Stress Response

The nucleolus is a dynamic structure within the nucleus primarily involved in ribosome biogenesis. Disruptions to nucleolar function or ribosome biogenesis can trigger a nucleolar stress response, which can lead to cell cycle arrest or apoptosis, often via activation of the tumor suppressor protein p53. nih.govnih.govaacrjournals.org Emerging evidence indicates that this compound, unlike cisplatin or carboplatin, can induce cytotoxicity by specifically disrupting ribosome biogenesis and triggering nucleolar stress. nih.govnih.govbiorxiv.orgresearchgate.net

This compound causes early nucleolar disruption, characterized by the inhibition of ribosomal RNA (rRNA) synthesis and the relocalization of nucleolar proteins like nucleophosmin (NPM1). nih.govnih.govbiorxiv.org These effects can occur at concentrations below those required for significant DNA damage, suggesting that nucleolar stress is an important and potentially early event in this compound's mechanism of action. nih.govnih.gov

The induction of nucleolar stress by this compound appears to be linked to DNA damage signaling involving ATM and ATR kinases, although it does not necessarily involve substantial nucleolar DNA damage itself. biorxiv.org The nonlabile diaminocyclohexane (DACH) ligand of this compound has been identified as important for its ability to induce nucleolar stress. nih.gov Proteomic profiling of cells treated with this compound has revealed downregulation of ribosomal proteins, further supporting the notion of disrupted ribosome biogenesis and nucleolar stress as key responses. aacrjournals.org This nucleolar and ribosomal stress can subsequently trigger apoptosis through both p53-dependent and independent pathways. aacrjournals.org

Enhanced Tolerance to Platinum-DNA Adducts

Enhanced tolerance refers to the ability of resistant cells to endure the presence of platinum-DNA adducts without triggering the normal cell death pathways. While this compound forms DNA adducts that block replication and transcription, resistant cells can develop mechanisms to bypass these lesions or tolerate their presence, allowing for continued cell division. Studies have shown that resistant cell lines can exhibit increased tolerance to adducts in DNA. nih.gov This tolerance can range from 3.1 to 7.6-fold in some resistant sub-lines. nih.gov This suggests that even if adducts are formed, the cellular machinery in resistant cells is less sensitive to their cytotoxic effects.

Upgraded Excision Repair Mechanisms (e.g., ERCC1 pathway)

The nucleotide excision repair (NER) pathway is a major DNA repair mechanism involved in removing bulky DNA lesions, including those formed by platinum compounds like this compound. aacrjournals.orgiiarjournals.org The excision repair cross-complementing group 1 (ERCC1) protein, in complex with XPF, plays a critical role in the NER pathway by creating an incision 5' to the damaged site. iiarjournals.orgecancer.orgiiarjournals.orgmdpi.com

Increased activity or expression of the NER pathway, particularly involving ERCC1, has been strongly implicated in this compound resistance. iiarjournals.orgecancer.orgiiarjournals.orgmdpi.com Studies have demonstrated that this compound treatment can induce ERCC1 gene expression in resistant, but not sensitive, colorectal cancer cell lines. iiarjournals.orgiiarjournals.org This induction of ERCC1 mRNA and protein in resistant cells suggests that the NER pathway is upregulated in response to this compound-induced DNA damage, leading to more efficient repair and thus resistance. iiarjournals.orgiiarjournals.org

The level of ERCC1 expression has been shown to correlate with the effectiveness of this compound treatment in patients with colorectal cancer. ecancer.org High levels of ERCC1 expression are associated with reduced sensitivity to this compound. ecancer.orgmdpi.com

Furthermore, studies using siRNA-mediated silencing of ERCC1 have shown that reducing ERCC1 levels in resistant cell lines can restore sensitivity to this compound, leading to increased apoptosis. iiarjournals.orgiiarjournals.org This provides strong evidence for the direct role of ERCC1 in mediating this compound resistance.

Replication Bypass Mechanisms

Replication bypass, also known as translesion synthesis (TLS), is a mechanism where specialized DNA polymerases can replicate past DNA lesions that would normally stall the high-fidelity replicative polymerases. This process can contribute to drug resistance by allowing cells with damaged DNA to continue dividing.

Studies suggest that replication bypass mechanisms can discriminate between cisplatin and this compound adducts. aacrjournals.org Human DNA polymerases such as pol β, pol γ, and pol η have been shown to replicate past this compound-GG adducts more efficiently than cisplatin-GG adducts in vitro. aacrjournals.orgnih.govaacrjournals.org The bulky diaminocyclohexane (DACH) ligand of this compound may influence how these polymerases interact with the adducts, potentially facilitating bypass. nih.govpatsnap.com Overexpression of certain polymerases involved in bypass has been linked to this compound resistance in some cancer cell lines. aacrjournals.org

Decreased Cellular Uptake Mechanisms

Reduced cellular uptake of this compound is a documented mechanism of resistance. nih.govmdpi.comaacrjournals.orgresearchgate.netnih.govnih.gov Studies have shown that this compound-resistant cell lines exhibit significantly lower intracellular accumulation of the drug compared to sensitive cell lines. nih.govaacrjournals.orgnih.govmdpi.com This decreased uptake can be a significant factor, sometimes accounting for a substantial reduction in intracellular platinum levels. nih.gov

Several transporters are involved in the cellular uptake of platinum compounds, including organic cation transporters (OCTs) and the human copper transporter 1 (hCTR1). mdpi.comresearchgate.net Changes in the expression levels or function of these transporters can lead to decreased this compound influx. For instance, reduced expression of OCT1-3 has been correlated with decreased cellular this compound accumulation and resistance in colorectal cancer cell lines. mdpi.comnih.gov

Increased Cellular Efflux Mechanisms

In addition to decreased uptake, increased efflux of this compound from the cell can also contribute to lower intracellular drug concentrations and thus resistance. Efflux transporters, particularly ATP-binding cassette (ABC) transporters, can actively pump platinum compounds out of the cell. mdpi.comresearchgate.net

ATPases like ATP7A and ATP7B have been implicated in the intracellular trafficking and efflux of platinum drugs, including this compound. mdpi.comresearchgate.netnih.gov Increased expression of ATP7A has been shown to mediate resistance to this compound in ovarian cancer cells. aacrjournals.org This increased expression can lead to increased sequestration of platinum into vesicular fractions and reduced net accumulation in the cytoplasm and nucleus. aacrjournals.org

Another efflux transporter, ABCC10 (MRP7), has also been identified as a mediator of this compound efflux. nih.gov Higher expression of ABCC10 in colorectal cancer patients is associated with a greater likelihood of relapse and metastasis. nih.gov Knockdown of ABCC10 in resistant colorectal cancer cells increases intracellular this compound accumulation and enhances sensitivity to the drug, indicating that ABCC10-mediated efflux is a mechanism of resistance. nih.gov

Drug Inactivation Processes (e.g., Glutathione Binding, Metallothionein Segregation)

One of the key mechanisms by which cancer cells develop resistance to this compound is through drug inactivation. This can occur via the binding of this compound to intracellular molecules like glutathione (GSH) and metallothioneins (MTs). Once this compound enters the cytoplasm, it can undergo hydration, which facilitates its reaction with thiol-containing molecules such as GSH or metallothioneins. aacrjournals.orgresearchgate.net Binding to these molecules can effectively sequester the drug, preventing it from reaching its DNA target and forming cytotoxic adducts. researchgate.netnih.gov This decreased intracellular concentration of active platinum compounds contributes to reduced drug efficacy and the development of resistance. aacrjournals.orgdergipark.org.tr Studies have reported conflicting results regarding the precise association between the levels or activity of GSH and this compound resistance in vitro. aacrjournals.orgresearchgate.net

Role of Organic Cation Transporters (OCTs) and ABC Transporters

Cellular accumulation of this compound is a critical determinant of its efficacy, and alterations in drug transport proteins play a significant role in resistance. This compound uptake can be mediated by organic cation transporters (OCTs), specifically OCT1, OCT2, and OCT3 (SLC22A1-3). nih.govaacrjournals.org Studies have shown that the expression levels of OCTs can positively correlate with this compound absorption and sensitivity. rsc.org Conversely, decreased expression or function of these uptake transporters can lead to reduced intracellular drug concentrations and contribute to resistance. researchgate.net For instance, the transporter protein OCT-1 has been found to be present in this compound-sensitive colon cancer cells but absent in drug-resistant cells. researchgate.net

Efflux transporters, particularly those belonging to the ATP-binding cassette (ABC) transporter superfamily, are also implicated in this compound resistance. aacrjournals.orgrsc.org These transporters can actively pump drugs out of the cell, thereby lowering intracellular drug accumulation. rsc.org The ABCC family of transporters, also known as multidrug resistance proteins (MRPs), are involved in the glutathione (GSH)-mediated export of platinum drugs, including this compound. aacrjournals.orgresearchgate.net Overexpression of certain ABC transporters, such as ABCC2, ABCC3, and ABCG2, has been demonstrated to be beneficial for the efficacy of this compound in some cell lines, suggesting their role in transport-mediated resistance. oup.comresearchgate.net However, the association between the expression of certain ABC transporters like ABCB1 (MDR1) and this compound resistance has shown inconsistent results, highlighting the need for further investigation. researchgate.net

Resistance to Apoptosis

Resistance to this compound-induced apoptosis is a significant mechanism of acquired resistance. elifesciences.orgresearchgate.net This can involve alterations in the expression or function of key proteins that regulate the apoptotic cascade. Proteins involved in the intrinsic apoptotic pathway, such as members of the Bcl-2 family and the tumor suppressor p53, are often deregulated in drug-resistant cancers. mdpi.com For example, studies have shown that activated AKT can directly influence apoptotic pathway regulators like Bcl-2 family members, and PI3K/AKT signaling can increase Bcl-2 expression and activity, promoting cell survival and reducing chemotherapy-induced apoptosis. mdpi.com Alterations in the balance between pro-apoptotic (e.g., Bax, BBC3/PUMA) and anti-apoptotic (e.g., Bcl-2, Bcl-XL) proteins can contribute to an impaired apoptotic response. nih.govresearchgate.net Loss of Bax expression due to mutation has been observed in some this compound-resistant cell lines, suggesting a role for altered mitochondrial-mediated apoptosis in resistance. researchgate.net Impairment of the extrinsic apoptotic pathway has also been implicated, with overexpression of proteins like MMP7, which can degrade FasL, preventing apoptosis progression. researchgate.net

Autophagy Modulation in Resistance

Autophagy, a cellular process involving the degradation and recycling of damaged organelles and proteins, can play a dual role in cancer, sometimes promoting cell survival and sometimes cell death. In the context of this compound resistance, autophagy is often upregulated in tumor cells in response to chemotherapy and can contribute to resistance. researchgate.netnih.gov this compound has been shown to modulate autophagy, leading to the development of resistance. mdpi.com For instance, this compound can trigger AMPK signaling and inhibit mTOR signaling to induce autophagy. mdpi.com Studies in this compound-resistant gastric cancer cells have shown increased autophagy, suggesting it may be a key factor in resistance development. mdpi.com Autophagic cell death, which includes autophagy-associated apoptosis, can facilitate cellular resistance to platinum therapy and drug resistance. mdpi.com Inhibition of autophagy has been shown in some research to reverse or overcome this compound resistance. nih.govnih.gov Mechanical stress in the tumor microenvironment can also trigger autophagy activation, which is correlated with increased resistance to this compound treatment. nih.gov

PI3K/AKT Signaling Pathway Activation

Hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is frequently linked to this compound resistance. mdpi.commdpi.comnih.gov This pathway is a key regulator of cell survival, proliferation, and apoptosis. nih.govspandidos-publications.com Activated AKT, phosphorylated by PI3K, can directly influence apoptotic regulators, increasing anti-apoptotic protein activity and promoting cell survival, thereby lowering chemotherapy-induced apoptosis. mdpi.comnih.gov Studies have demonstrated increased constitutive activity of the PI3K/AKT pathway in cancer cells with acquired resistance to this compound. dovepress.com Inhibition of the PI3K/AKT pathway has been shown to increase the sensitivity of cancer cells to this compound. nih.govspandidos-publications.com For example, studies in cholangiocarcinoma and liver cancer cells have shown that inhibiting PI3K or its downstream target mTOR can enhance this compound efficacy. nih.govspandidos-publications.com The downregulation of PTEN, a negative regulator of the PI3K/AKT pathway, has also been observed in this compound-resistant cells, contributing to increased PI3K/AKT phosphorylation and reduced response to this compound-induced cell death. nih.gov

Table 1: and Associated Factors

Table 2: Research Findings on PI3K/AKT Signaling in this compound Resistance

NF-κB Signaling Alterations

The NF-κB signaling pathway plays a crucial role in regulating numerous cellular functions, including those that contribute to tumor drug resistance. wjgnet.com Activation of the NF-κB pathway can enhance the expression of anti-apoptotic proteins, thereby making cancer cells more resistant to chemotherapy-induced apoptosis. researchgate.net Studies have shown that chemotherapy-induced activation of NF-κB signaling contributes to heightened drug resistance in tumor cells. wjgnet.com For instance, in this compound-resistant colorectal cancer cells, upregulation of NF-κB phosphorylation has been observed, leading to enhanced expression of ABCG2, a transporter protein, and subsequent attenuation of endoplasmic reticulum stress and inhibition of apoptosis. researchgate.net The NF-κB pathway can also interact with other signaling cascades, such as the PI3K-AKT pathway, forming extensive regulatory networks that influence tumor cell behavior, including growth, resistance to apoptosis, and migration. wjgnet.com PIPKIγ has been identified as a critical gene related to this compound resistance in colorectal cancer, promoting the expression of PD-L1 via activation of the NF-κB signaling pathway. thno.org Knockdown of PIPKIγ significantly down-regulated the phosphorylated level of P65, a component of NF-κB, while overexpression increased it, consistently affecting NF-κB transcriptional activity. thno.org

Gene Expression Profile Changes (e.g., lncRNA HOTAIR)

Hypoxic Conditions and Chemoresistance

The tumor microenvironment, particularly the presence of hypoxic (low oxygen) conditions, plays a significant role in the development of chemoresistance to various agents, including this compound. Hypoxia is a common feature of solid tumors and is often associated with poor prognosis and reduced sensitivity to both chemotherapy and radiotherapy mdpi.comcapes.gov.brnih.gov. Cancer cells that adapt to hypoxic environments can develop resistance to this compound through a variety of mechanisms spandidos-publications.comresearchgate.net.

Detailed research findings highlight several pathways by which hypoxia contributes to this compound resistance:

Hypoxia-Inducible Factors (HIFs): HIFs, particularly HIF-1α, are key regulators of the cellular response to hypoxia mdpi.comresearchgate.net. Under hypoxic conditions, HIF-1α is stabilized and promotes the transcription of numerous genes involved in processes such as cell metabolism, proliferation, angiogenesis, and drug resistance researchgate.netnih.gov. HIF-1α has been shown to induce this compound resistance in colorectal cancer (CRC) cells researchgate.netnih.gov. This can occur through various mechanisms, including the upregulation of ATP-Binding Cassette (ABC) transporters like ABCB1 (MDR1), ABCC1 (MRP1), and ABCG2 (BCRP), which actively pump chemotherapeutic drugs out of the cells, thereby reducing intracellular drug concentration mdpi.comzlfzyj.comdovepress.com. Studies in hepatic carcinoma cells have also demonstrated that hypoxia-induced upregulation of HIF-1α correlates with increased expression of MDR1, MRP1, and BCRP1, contributing to this compound resistance zlfzyj.com.

Modulation of Apoptosis: Hypoxia can enhance the anti-apoptotic potential of cancer cells, making them less susceptible to this compound-induced cell death mdpi.com. HIF-1 can induce the expression of anti-apoptotic proteins like Survivin and suppress pro-apoptotic proteins like Caspase-9 mdpi.com. Additionally, hypoxia can decrease the level of apoptosis induced by this compound in CRC cells nih.gov.

Signaling Pathways: Hypoxia can activate various signaling pathways that promote drug resistance. For instance, HIF is known to cause this compound resistance in colorectal cancer by inducing miR-338-5p expression, which promotes IL-6 signaling. This, in turn, suppresses apoptosis via the STAT3/BCL2 pathway mdpi.comnih.gov. The IL-6/STAT3/Bcl2 pathway has been identified as a critical mechanism of hypoxia-induced drug resistance in CRC cells nih.gov. Studies have also investigated the role of JNK signaling; hypoxia-induced JNK activation was associated with resistance to this compound in colon cancer cell lines aacrjournals.org.

Non-Coding RNAs: Long non-coding RNAs (lncRNAs) have been implicated in hypoxia-mediated this compound resistance. For example, studies have shown that hypoxia increases the expression of HOX transcript antisense RNA (HOTAIR) in CRC cells, and HOTAIR contributes to this compound resistance by modulating the expression of zinc finger E-box binding homeobox 1 (ZEB1) through negative regulation of miR-1277-5p researchgate.netresearchgate.net. MicroRNAs (miRNAs) also play a role; research suggests that under hypoxic conditions, P53 may induce this compound resistance through the activation of miR-23a spandidos-publications.com.

Drug Penetration: While biological mechanisms are significant, impaired drug penetration into hypoxic regions of tumors due to the distance from blood vessels also contributes to reduced this compound effectiveness mdpi.comnih.govdovepress.com. Studies using three-dimensional spheroids have shown that a sensitivity gradient exists, with hypoxic regions being less sensitive to this compound, which correlates with lower levels of platinum-bound DNA adducts nih.govnih.gov. However, the resistance observed in hypoxic sub-populations often exceeds what can be explained by reduced drug penetrance alone, indicating the involvement of other cellular adaptive responses nih.govnih.gov.

Data from various studies illustrate the impact of hypoxia on this compound sensitivity in different cancer cell lines. For example, in HCT116 colorectal cancer cells, the IC50 (the concentration of drug required for 50% inhibition of cell growth) for this compound is significantly higher under hypoxic conditions compared to normoxic conditions nih.gov.

Here is a table summarizing representative data on this compound sensitivity under normoxic and hypoxic conditions:

Note: IC50 values can vary depending on the assay method and experimental conditions used in different studies.

The data consistently demonstrate that hypoxic conditions lead to reduced sensitivity or increased resistance to this compound in various cancer cell lines, particularly those of colorectal origin nih.govspandidos-publications.comnih.govresearchgate.net. This underscores the importance of understanding and targeting hypoxia-induced resistance mechanisms to improve the efficacy of this compound-based chemotherapy.

This compound-DNA Adduct Levels in Peripheral Blood Mononuclear Cells (PBMCs)

This compound exerts its cytotoxic effects through the formation of covalent drug-DNA adducts. The level of these adducts in tumor cells is hypothesized to correlate with treatment response. However, obtaining tumor biopsies can be challenging. Research suggests that this compound-DNA adduct levels in peripheral blood mononuclear cells (PBMCs) may serve as a surrogate biomarker for tumor DNA adducts and predict response to this compound-based regimens like FOLFOX (a combination of leucovorin calcium, fluorouracil, and this compound). nih.govnih.govosti.govaacrjournals.orgescholarship.orgresearchgate.net

Studies have investigated the relationship between this compound-DNA adduct levels in PBMCs and tumor response in colorectal cancer patients. One pilot clinical study involving six colorectal cancer patients treated with FOLFOX chemotherapy found a significant correlation between this compound-DNA adduct levels in PBMCs and the mean tumor volume change of evaluable target lesions. nih.govnih.govosti.govaacrjournals.org This study utilized a diagnostic microdosing approach with 14C-labeled this compound and accelerator mass spectrometry (AMS) for sensitive quantification of adduct levels. nih.govosti.govaacrjournals.org Adduct levels induced by sub-therapeutic microdoses were found to be linearly proportional to those induced by therapeutic doses in both cell culture experiments and patient samples, suggesting the potential utility of diagnostic microdosing for predicting therapeutic adduct levels and treatment response. nih.govosti.govaacrjournals.org

Data from this pilot study indicated that PBMC adduct levels significantly correlated with tumor shrinkage (microdose: R2 = 0.82, p = 0.033; therapeutic dose: R2 = 0.65, p = 0.099). aacrjournals.org This supports the hypothesis that this compound-DNA adduct levels in PBMCs are proportional to tumor shrinkage caused by FOLFOX therapy and can potentially predict response. nih.govnih.govosti.gov

Oxidative Phosphorylation Activity

Oxidative phosphorylation (OXPHOS) is the primary method of ATP synthesis in aerobic conditions. Recent research suggests that the activity of oxidative phosphorylation pathways may serve as a predictive biomarker for this compound response in colorectal cancer. Studies analyzing patient samples and this compound-resistant and -sensitive cell lines have identified oxidative phosphorylation pathways as potentially valuable predictive biomarkers. researchgate.netnih.govresearchgate.netmdpi.comthno.org

Research using datasets from patients treated with this compound has indicated that non-responding patients tend to exhibit low oxidative phosphorylation activity. researchgate.netnih.govmdpi.com This suggests that low OXPHOS activity may be associated with a poor prognosis in the context of this compound treatment. researchgate.netnih.gov Analysis of differential gene expression between this compound non-responder and responder colorectal cancer patients has highlighted OXPHOS KEGG pathways as having predictive value, with a high area under the curve (AUC = 0.843). researchgate.netnih.govresearchgate.netmdpi.com

Machine Learning-Derived Molecular Signatures (e.g., FOLFOXai)

Genetic Profiles (e.g., Single Nucleotide Polymorphisms - SNPs)

Genetic variations, particularly single nucleotide polymorphisms (SNPs), in genes involved in this compound transport, metabolism, detoxification, and DNA repair have been investigated as potential predictors of OXAIPN susceptibility. nih.govnih.govmdpi.comnih.govuspharmacist.comtandfonline.com

Polymorphisms in genes encoding drug transporters, such as ATP-binding cassette (ABC) transporters (ABCC1, ABCG1), have been hypothesized to influence intracellular this compound concentrations, potentially affecting neurotoxicity risk. mdpi.comnih.govuspharmacist.com Specific SNPs in ABC transporters, including rs717620, rs8187710, rs2231142, and rs1045642, have been suggested to play a role. nih.gov

Variations in genes involved in detoxification enzymes, such as glutathione S-transferases (GSTA1, GSTM1/3, GSTP1, GSTT1) and myeloperoxidase (MPO), have also been studied. mdpi.comuspharmacist.comtandfonline.com The GSTP1 rs1694 SNP has been a focus of many investigations, with some studies suggesting it confers protection against chemotherapy-induced peripheral neuropathy (CIPN), while others have reported conflicting results depending on the patient population. tandfonline.com

SNPs in DNA repair pathway genes, including those in the nucleotide excision repair (NER) pathway like ERCC1, XPA, XRCC1, and ERCC2 (XPD), have been explored for their association with OXAIPN. frontiersin.orgresearchgate.netmdpi.comuspharmacist.comtandfonline.com For example, the ERCC1 rs11615 SNP has been associated with early onset of grade 1 CIPN in some studies, although other studies have not found a significant association. tandfonline.com Higher levels of ERCC1 protein, potentially influenced by the ERCC1-118 T/T genotype, may lead to less this compound toxicity due to increased DNA repair. uspharmacist.com

Other genes implicated in neuropathy and investigated for SNPs include sodium channels (SCN4A, SCNA10A, SCN9A), although some SNPs like SCN2A R19K have not been found to be related to OXAIPN manifestation. biorxiv.orgmdpi.com Proteins like OCT2, Caspase-3, GAP43, and pNfH are also known to be involved in peripheral neurotoxicity upon this compound administration. biorxiv.org

Epigenetic Profiles

Epigenetic modifications, such as DNA methylation and histone modifications, play a crucial role in regulating gene expression and have been implicated in cancer development and drug resistance. pensoft.netnih.govirjournal.org Aberrant epigenetic profiles can influence the sensitivity of cancer cells to chemotherapeutic agents like this compound. mdpi.com

DNA methylation, primarily occurring at CpG dinucleotides, can lead to gene silencing, particularly in CpG islands located in gene promoters. nih.govnih.gov Studies have investigated the role of DNA methylation in this compound resistance. For instance, hypermethylation of the GSTP1 promoter, a gene encoding a phase II drug-metabolizing enzyme, has been suggested as a potential epigenetic biomarker. pensoft.net Downregulation or hypermethylation of GSTP1 can affect the metabolism of this compound. pensoft.net Another gene where promoter methylation has been associated with reduced expression in this compound-resistant cells is Casp8AP2. nih.gov

Histone modifications, including acetylation and methylation, also impact chromatin structure and gene transcription. pensoft.netnih.gov While less studied than DNA methylation as biomarkers for this compound response or resistance, aberrant histone modification patterns are known to contribute to cancer pathogenesis and can influence the cellular response to chemotherapy. nih.gov Research suggests that drug exposure can lead to epigenomic changes that contribute to individual variations in chemotherapy response. nih.gov

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, are another component of the epigenetic landscape. irjournal.orgfrontiersin.org Changes in miRNA expression profiles have been observed in colorectal cancer patients receiving this compound-based chemotherapy and are being investigated as potential biomarkers for chemoresistance. frontiersin.org A study identified a panel of six plasma exosomal miRNAs (miR-100, miR-92a, miR-16, miR-30e, miR-144-5p, and let-7i) that could differentiate between chemoresistant and chemosensitive patients with higher accuracy than traditional tumor biomarkers. frontiersin.org

Epigenetic alterations can affect various pathways involved in this compound resistance, including DNA repair, apoptosis, and drug transport. researchgate.netmdpi.com Understanding these epigenetic modifications may help identify patients likely to benefit from this compound treatment and potentially lead to the development of epigenetic-based therapeutic strategies to overcome resistance. nih.govnih.gov

Neurophysiological Indicators (e.g., Thermal Detection Thresholds, Quantitative Sensory Testing)

This compound-induced peripheral neurotoxicity (OIPN) is a common and often dose-limiting side effect of this compound, characterized by both acute and chronic symptoms. nih.govnih.govfrontiersin.org Neurophysiological assessments, such as Quantitative Sensory Testing (QST) and nerve excitability testing, can provide objective measures of nerve function and potentially serve as indicators for the risk and severity of OIPN. nih.govnih.govwhiterose.ac.uknih.gov

Quantitative Sensory Testing (QST) is a noninvasive method used to assess the function of sensory nerve fibers by measuring thresholds for detecting and perceiving different stimuli, including thermal (cold and warm sensation, cold and heat pain) and mechanical (touch, vibration, pinprick). nih.govwhiterose.ac.ukmedoc-web.comaacrjournals.org Changes in thermal detection thresholds, such as cold and warm sensation thresholds, have been evaluated in patients undergoing this compound treatment. nih.govmedoc-web.com Elevated cold and warm detection thresholds have been observed in patients, indicating sensory deficits. nih.gov

Studies have utilized QST to detect subclinical neuropathy early in the course of this compound treatment and to predict the development of clinically overt chronic neuropathy. nih.gov For example, patients who developed thermal and cutaneous sensory deficits during the first cycle of this compound infusion were more likely to experience grades 2 and 3 neuropathy at one year. nih.gov Specific QST measures, such as cold pain thresholds and rheobase (a measure of axonal excitability), have been suggested as potentially more sensitive tools for detecting long-term this compound peripheral nerve complications compared to standard clinical grading scales like the Common Terminology Criteria for Adverse Events (CTCAE). medoc-web.com

Nerve excitability testing assesses the physiological properties of peripheral nerves, including ion channel function. nih.govplos.org this compound is known to modulate voltage-gated sodium channels, which contributes to neuronal hyperexcitability and the acute symptoms of OIPN. mdpi.comnih.gov Changes in axonal excitability parameters, such as refractoriness and superexcitability, have been observed following this compound infusion. nih.govplos.org While some studies suggest that acute changes in sensory excitability during early treatment cycles might predict final clinical outcome, others indicate that thermal threshold impairment might emerge too late to guide early intervention for neuropathy prophylaxis. nih.govoup.com

Neurophysiological indicators provide objective data on nerve function and can complement clinical assessments in monitoring for OIPN. nih.govnih.gov However, further research is needed to fully establish their role as predictive biomarkers for this compound response and resistance in the context of managing neurotoxicity.

Polymeric Nanoparticles and Micelles

Polymeric nanoparticles and micelles, formed by the self-assembly of amphiphilic block or graft copolymers, have been explored as carriers for this compound. jst.go.jpnih.gov These systems can encapsulate this compound within their core-shell structure, providing advantages such as improved drug solubility and stability. nih.gov Studies have shown that this compound-loaded polymeric micelles can exhibit enhanced internalization by cancer cells, leading to increased intracellular drug accumulation. nih.govnih.gov For instance, stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles loaded with this compound demonstrated excellent internalization ability and increased this compound accumulation in colorectal cancer cells and tissues in a xenograft mouse model. nih.govnih.gov This led to effective suppression of tumor growth and a reduction in cancer stem-like cell populations compared to free this compound. nih.govnih.gov Another study investigated mPEG-b-P(D,L)LA nanoparticles for this compound delivery, achieving an encapsulation efficiency of 76% with a drug loading content of 3.8 wt.%. mdpi.com These nanoparticles maintained a uniform size and structure after drug loading. mdpi.com Liver-targeting micelles loaded with this compound, prepared using glycyrrhetinic acid-conjugated and stearic acid-grafted chitosan (GA-CS-SA), showed a uniform size of 138.6 ± 0.72 nm and an encapsulation efficiency of up to 71.7 ± 0.46%. tandfonline.com These liver-targeting micelles altered the in vivo distribution of this compound, increasing its content in the liver and spleen while reducing it in the heart and kidney, and demonstrated sustained in vitro release. tandfonline.com

Here is a summary of some research findings on polymeric nanoparticles and micelles for this compound delivery:

Liposomes

Liposomes, artificial vesicles composed of one or more phospholipid bilayers, are widely explored as drug carriers for this compound. jst.go.jpjst.go.jpnih.gov Their biocompatibility, biodegradability, and ability to encapsulate both hydrophilic and hydrophobic drugs make them suitable for this compound delivery. jst.go.jpnih.gov PEGylated liposomes, modified with polyethylene glycol (PEG), can prolong the circulation half-life of encapsulated this compound and enhance its accumulation in tumor tissues via the EPR effect. jst.go.jpjst.go.jpnih.gov Studies have shown that PEGylated liposomal this compound can significantly enhance drug accumulation in tumor tissues and improve therapeutic efficacy in xenograft models. jst.go.jpjst.go.jp For instance, a formulation composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and mPEG2000-distearoylphosphatidylethanolamine (DSPE) showed improved efficacy in tumor-bearing mice. jst.go.jp Lipoxal™, a PEGylated liposome formulation of this compound, has shown reduced adverse reactions in animal studies while maintaining similar efficacy to the free drug. jst.go.jp Encapsulation efficiency of this compound in liposomes can vary depending on the preparation technique, with reported efficiencies ranging from approximately 30% to 69.1%. nih.gov Thermosensitive liposomes have also been developed for this compound delivery, designed to release the drug in response to mild hyperthermia at the tumor site. dovepress.comresearchgate.net These systems have shown significantly higher cytotoxicity at 42°C compared to 37°C and enhanced tumor accumulation and retention in vivo. dovepress.comresearchgate.net

Here is a summary of some research findings on liposomes for this compound delivery:

Carbon Nanotubes

Carbon nanotubes (CNTs), with their unique physical and chemical properties, including high surface area and structural robustness, have been investigated as nanovectors for this compound delivery. jst.go.jpiau.ir Both single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) have been explored. jst.go.jpiau.irnih.govrsc.org this compound can be encapsulated within the inner cavity of CNTs or conjugated to their surface. iau.irnih.gov Functionalization of CNTs, such as PEGylation, can improve their water solubility and biocompatibility, and influence the drug release rate. jst.go.jpnih.gov Studies using computational methods have indicated that this compound can be encapsulated within SWCNTs, with stronger affinity for semiconducting nanotubes. iau.ir Experimental studies with PEGylated MWCNTs have demonstrated sustained release of this compound and improved cytotoxicity against cancer cells in vitro. nih.govresearchgate.net For example, PEGylated MWCNT-Oxaliplatin showed sustained release with only 34% of the drug released within 6 hours. nih.govresearchgate.net Another study involving this compound encapsulated in PEGylated MWNTs decorated with superparamagnetic iron oxide (SPIO) also demonstrated sustained release, with only 36.25% released within 12 hours and 55.48% over 144 hours. rsc.org

Here is a summary of some research findings on carbon nanotubes for this compound delivery:

Biomimetic Magnetic Nanoparticles

Biomimetic magnetic nanoparticles (BMNPs) represent an innovative approach for targeted this compound delivery, particularly for applications like colon cancer therapy. csic.esnih.govmdpi.com These nanoparticles, often mediated by proteins like MamC, can be coupled with this compound to form nanoassemblies. csic.esnih.govmdpi.com The interaction between this compound and BMNPs can be based on electrostatic forces, maintaining stability at physiological pH. csic.esnih.govresearchgate.net A key feature of some BMNPs is their pH-responsive behavior, where the release of this compound is triggered by the lower pH values found in the tumor microenvironment. csic.esnih.govresearchgate.netnih.gov This release can be further enhanced by hyperthermia. csic.esnih.govresearchgate.netnih.gov Studies have shown that this compound-BMNP nanoassemblies can improve the toxicity of the drug against tumor cells, potentially due to enhanced internalization via endocytosis. csic.esnih.govresearchgate.netnih.gov Enveloping this compound-BMNP nanoassemblies in liposomes, particularly PEGylated ones, has been shown to improve biocompatibility and cellular uptake while maintaining cytotoxic activity. mdpi.com

Here is a summary of some research findings on biomimetic magnetic nanoparticles for this compound delivery:

pH-Responsive Systems

Tumor tissues often exhibit a lower pH compared to normal physiological environments due to increased glycolysis and poor perfusion. nih.gov This difference in pH can be exploited to design drug delivery systems that selectively release this compound in the acidic tumor microenvironment.

One approach involves the use of pH-sensitive nanostructures. For instance, pH-sensitive nanostructures have been prepared for the co-delivery of this compound and microRNA (miRNA) in head and neck cancer treatment. nih.gov Studies have shown that some nanoparticles release drugs in response to pH 5.5. nih.gov In another example, magnetic metal-organic frameworks synthesized from a copper organic framework and Fe₃O₄ magnetic nanoparticles have been explored as pH-responsive nanocarriers for this compound. In vitro drug release experiments demonstrated that approximately 35% of this compound was released in simulated gastric fluid (pH 1.2) over 30 minutes, while a significantly higher release of 85% occurred in simulated intestinal fluid (pH 7.4) over 9 hours. researchgate.net

Complexation-based pH-responsive systems have also been developed. A system based on the host-guest encapsulation of this compound by carboxylatopillar researchgate.netarene (CP6A), a pH-responsive receptor, has shown promise. nih.govrsc.org The binding affinity of CP6A for this compound is pH-sensitive; the association constant (Ka) at pH 7.4 is reported to be 24 times larger than that at pH 5.4. nih.govrsc.org This pH-dependent binding allows for the protection of this compound in the bloodstream (physiological pH) and its effective release in the acidic tumor environment. nih.govresearchgate.net This approach has been shown to increase the inherent stability of this compound in plasma by 2.8-fold over a 24-hour incubation period and enhance its in vivo anticancer activity in a mouse model. researchgate.netrsc.org

Another dual-responsive system utilizing pH and near-infrared (NIR) light incorporates this compound and naringin into a hydrogel composed of graphene oxide, sodium alginate, and carboxymethyl chitosan. This system aims for precise drug release in colorectal tumor therapy based on both pH changes and NIR irradiation. farmaciajournal.comfarmaciajournal.com

Redox-Responsive Systems

Cancer cells often exhibit a higher concentration of reducing agents, such as glutathione (GSH), compared to normal cells. frontiersin.org This difference in redox potential can be utilized for targeted drug release. Redox-responsive drug delivery systems typically incorporate bonds that are cleaved in a reducing environment, leading to the dissociation of the carrier and release of the encapsulated drug. frontiersin.orgmdpi.com

One study explored a redox-responsive polymeric nanocomplex for the co-delivery of a cytotoxic protein (RNase A nitrophenylboronic conjugate, RNBC) and this compound(IV) prodrug. acs.org This nanocomplex, fabricated using polyethylenimine cross-linked by the this compound(IV) prodrug, was designed to dissociate in the highly reducing intracellular environment of cancer cells, releasing both the protein and active this compound. acs.org The activity of the encapsulated RNBC was recovered by the catalytic production of hydrogen peroxide from glucose oxidase (GOD) and glucose, which are overexpressed in cancer cells. acs.org Monitoring changes in nanoparticle size confirmed that the nanocomplex dissociates in a reducing environment, releasing the active drug and protein. acs.org

Another approach involves platinum(IV) prodrugs of this compound. These complexes, with additional ligands in the axial positions, are kinetically more inert than their platinum(II) precursors, potentially reducing off-target interactions and enhancing bioavailability. acs.org Intracellular reduction is thought to convert the platinum(IV) prodrug to the cytotoxic platinum(II) complex, releasing the axial ligands. acs.org Some this compound(IV) complexes have been designed to be fluorescence responsive, allowing for the identification of hypoxia-dependent reduction in cancer cells. acs.org

Light- and Thermo-Sensitive Systems

Drug delivery systems responsive to external stimuli like light and heat offer the advantage of controlled drug release at a specific site and time. nih.govjst.go.jp

Thermosensitive liposomes have been investigated for this compound delivery. These liposomes are designed to release their encapsulated drug when exposed to a specific temperature range, often slightly above physiological temperature, which can be achieved through localized hyperthermia at the tumor site. nih.govdovepress.complos.org A study on this compound-loaded thermosensitive liposomes (LCTL) demonstrated almost complete release (around 80-70%) of the drug within 0.5 to 4 hours at 42°C, while only about 10% was released at 37°C after 24 hours. nih.govdovepress.com These liposomes also showed significantly higher cytotoxicity at 42°C compared to 37°C. nih.gov The addition of poloxamer 188 to thermosensitive liposome formulations has been shown to improve stability while maintaining rapid release at the triggered temperature. plos.orgnih.gov More than 90% of this compound was released within 10 minutes at 42°C from these formulations, with less than 15% released within 60 minutes at temperatures below 39°C. plos.orgnih.gov

Light-responsive systems, particularly those triggered by near-infrared (NIR) light, are also being explored, often in combination with other stimuli like pH. farmaciajournal.comfarmaciajournal.com These systems can utilize photothermal effects or photocleavable linkers to achieve controlled drug release upon irradiation with light of a specific wavelength.

Magnetically controlled this compound release systems have also been studied, offering advantages over conventional diffusion or thermal response methods. nih.gov Hybrid liposome-magnetic nanoparticles loaded with this compound showed a significant increase in this compound release (~18%) and lower cell viability after exposure to an alternating magnetic field (AMF). nih.gov

Non-enzymatic Biotransformation and Active Platinum Derivatives

This compound undergoes rapid and extensive non-enzymatic biotransformation in physiological solutions through the displacement of the labile oxalate ligand. fda.govpfizermedicalinformation.comaacrjournals.orgdrugbank.comnih.govnih.gov This process leads to the formation of several transient reactive species, including monoaquo and diaquo DACH platinum, which are capable of covalently binding with macromolecules, particularly DNA. fda.govpfizermedicalinformation.comdrugbank.comnih.govnih.gov

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients. pfizermedicalinformation.comaacrjournals.orgdrugbank.comnih.gov These derivatives include cytotoxic species such as monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum. pfizermedicalinformation.comdrugbank.comnih.gov A number of noncytotoxic, conjugated species are also formed during this biotransformation process. pfizermedicalinformation.comdrugbank.comnih.gov Unlike some other drugs, this compound biotransformation does not involve cytochrome P450-mediated metabolism. pfizermedicalinformation.comaacrjournals.orgdrugbank.comnih.govnih.gov

Platinum Elimination and Tissue Distribution

The primary route of platinum elimination following this compound administration is renal excretion. fda.govpfizermedicalinformation.comdrugbank.comnih.gov Within five days after a single 2-hour infusion, approximately 54% of the eliminated platinum is recovered in urine, while fecal excretion accounts for only about 2%. fda.govpfizermedicalinformation.comdrugbank.comnih.gov

Platinum is cleared from plasma at a rate (10-17 L/h) that is similar to or exceeds the average human glomerular filtration rate (GFR; 7.5 L/h). fda.govpfizermedicalinformation.comdrugbank.com The renal clearance of ultrafilterable platinum shows a significant correlation with GFR. fda.govpfizermedicalinformation.comdrugbank.com While clearance of ultrafilterable platinum may be decreased in patients with moderate renal impairment, this has not been consistently associated with increased drug toxicity. aacrjournals.org The effect of severe renal impairment on platinum clearance and toxicity is not fully established. aacrjournals.org Age, sex, and moderate hepatic impairment have not shown a significant effect on the clearance of ultrafilterable platinum. aacrjournals.org

Following distribution, platinum binds irreversibly and accumulates in various tissues. fda.govpfizermedicalinformation.comdrugbank.comtg.org.aunih.gov Long-term retention of platinum derivatives has been observed, with plasma concentrations of platinum in individuals previously exposed to this compound being significantly higher than in unexposed controls, even months after treatment cessation. nih.gov This retained platinum is found in both whole and ultrafilterable plasma, and risk factors for persistently high levels include decreased glomerular function and high cumulative dose. nih.gov

Drug-Drug Interaction Studies

Studies have investigated potential drug-drug interactions with this compound. No significant pharmacokinetic interaction has been observed between this compound (85 mg/m² infused every two weeks) and infusional fluorouracil. sanofi.us However, increases in fluorouracil plasma concentrations by approximately 20% have been noted with higher doses of this compound (130 mg/m² administered every three weeks). sanofi.us

In vitro studies have indicated that platinum is not displaced from plasma proteins by several commonly co-administered medications, including erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. sanofi.us Furthermore, this compound does not appear to inhibit human cytochrome P450 enzymes in vitro, suggesting it may be safely used with other drugs metabolized by this system when necessary. aacrjournals.orgnih.govnih.gov

While a comprehensive review identified numerous potential drug interactions with irinotecan, only one non-specific, clinically significant interaction was identified for this compound in the literature examined. nih.gov However, this compound requires close monitoring when given with other drugs as it can potentially enhance adverse effects or diminish therapeutic efficacy of certain agents. nih.gov Specific interactions to consider include those with QT-prolonging agents due to the reported risk of QT prolongation and Torsade de Pointes with this compound. sanofi.usnih.govsandoz.com Caution is also advised with medications associated with rhabdomyolysis when administered concurrently with this compound. sandoz.com

Ultraperformance Liquid Chromatography-Inductively Coupled Plasma Mass Spectrometry (UHPLC-ICP-MS)

UHPLC-ICP-MS is an advanced hyphenated technique increasingly utilized for the quantification and speciation of platinum compounds, including this compound, in biological matrices. nih.govauckland.ac.nznih.govrsc.org This method combines the high-resolution separation capabilities of Ultraperformance Liquid Chromatography (UHPLC) with the sensitive and element-specific detection of Inductively Coupled Plasma Mass Spectrometry (ICP-MS). auckland.ac.nznih.gov

UHPLC-ICP-MS allows for the separation of intact this compound from its transformation products and other platinum-containing species before detection by ICP-MS, which measures the platinum atom. nih.govrsc.org This provides a more specific quantification of the parent drug compared to methods that only measure total platinum. nih.govnih.gov

Methods utilizing UHPLC-ICP-MS for intact this compound quantification in human plasma have been developed and validated, demonstrating good accuracy and precision. auckland.ac.nznih.gov These methods often involve sample preparation steps such as protein precipitation before UHPLC separation on a C18 column and detection of platinum isotopes (e.g., m/z 195) by ICP-MS. nih.gov Limits of quantification in the nanomolar range have been achieved. auckland.ac.nznih.govrsc.org UHPLC-ICP-MS has been applied to determine intact this compound concentrations in patients undergoing chemotherapy and to study its degradation in vitro. nih.gov

Heart-cut 2D SEC-RP-LC-ICP-MS, a two-dimensional liquid chromatography approach coupled with ICP-MS, has also been introduced as a screening tool for metal-based anticancer drugs like this compound. rsc.org This method employs size-exclusion chromatography in the first dimension and reversed-phase liquid chromatography in the second, allowing for the quantification of free and intact metal-based drugs in biological matrices with minimal sample preparation. rsc.org

High-Performance Liquid Chromatography-Ultraviolet (HPLC-UV)

High-Performance Liquid Chromatography (HPLC) coupled with Ultraviolet (UV) detection is another chromatographic technique used for the quantification of this compound, particularly in pharmaceutical formulations and sometimes in biological samples, although its sensitivity may be lower compared to ICP-MS for biological matrices. ijsit.comnih.govresearchgate.netscilit.comresearchgate.net

RP-HPLC methods with UV detection at wavelengths such as 240 nm have been developed and validated for the assay of this compound. ijsit.comnih.govresearchgate.net These methods typically utilize reversed-phase columns and isocratic or gradient elution with mobile phases consisting of mixtures of water, methanol, or acetonitrile. ijsit.comnih.gov UV detection is possible because this compound contains a chromophore that absorbs UV light.

Accelerator Mass Spectrometry for DNA Adducts Quantification

Accelerator Mass Spectrometry (AMS) is an ultrasensitive analytical technique employed in pharmacological research to quantify the formation of DNA adducts by compounds like this compound. This compound, a platinum-based anticancer drug, exerts its cytotoxic effects primarily through the formation of covalent adducts with DNA, leading to the inhibition of DNA replication and transcription. wikipedia.orgnih.govaacrjournals.orgdrugbank.com Understanding the kinetics of this compound-DNA binding and the distribution of these adducts is crucial for elucidating its mechanism of action and identifying potential biomarkers for treatment response. nih.govaacrjournals.org

AMS offers exceptional sensitivity, capable of detecting attomole (10-18 mole) quantities of isotopes like 14C, which can be incorporated into the this compound molecule. osti.govaacrjournals.org This high sensitivity allows for the measurement of DNA adduct levels following administration of very low, sub-pharmacological "diagnostic microdoses" of 14C-labeled this compound. osti.govaacrjournals.org

Research utilizing AMS has investigated the kinetics of this compound-DNA adduct formation in both genomic DNA and human cancer cells. aacrjournals.org By labeling this compound with 14C on its carrier group, AMS can quantify the total amount of this compound-DNA adducts. aacrjournals.org Furthermore, coupling AMS with High-Performance Liquid Chromatography (HPLC-AMS) allows for the separation and discrimination of different types of this compound-DNA adducts, such as monoadducts, intrastrand, and interstrand diadducts, providing insights into the differential formation of these species over time. aacrjournals.orgdrugbank.com

Studies have applied AMS to measure this compound-DNA adduct distribution in various cancer cell lines, including platinum-sensitive testicular cancer cells (833K) and platinum-resistant breast cancer cells (MDA-MB-231). nih.govaacrjournals.org These studies have revealed cell-dependent differences in this compound-DNA adduct formation, suggesting that variations in adduction and/or accumulation of the drug in cellular DNA may contribute to the differential sensitivity of cancer cells to platinum treatment. nih.gov

In clinical pilot studies, AMS has been used to quantify this compound-DNA adduct levels in peripheral blood mononuclear cells (PBMC) from patients with colorectal cancer receiving FOLFOX therapy. osti.govaacrjournals.orgnih.gov These studies aimed to determine if adduct levels induced by diagnostic microdoses correlate with those induced by therapeutic doses and if they could serve as predictive biomarkers for response to FOLFOX therapy. osti.govaacrjournals.orgnih.gov Findings have indicated a significant correlation between this compound-DNA adduct levels in PBMC and tumor volume change, supporting the potential utility of diagnostic microdosing and AMS for predicting patient response and optimizing treatment strategies. osti.govnih.gov

Data from research using AMS has demonstrated a linear proportionality between this compound-DNA adduct levels induced by microdose and therapeutically relevant concentrations in both cell culture experiments and patient samples. osti.govaacrjournals.orgnih.gov

Solid-Phase Microextraction Coupled with Liquid Chromatography-Mass Spectrometry for Metabolic Fate Analysis

Solid-Phase Microextraction (SPME) coupled with Liquid Chromatography-Mass Spectrometry (LC-MS) is a valuable analytical approach for investigating the metabolic fate of this compound. This compound undergoes rapid and extensive non-enzymatic biotransformation in physiological solutions, leading to the formation of various platinum-containing derivatives. drugbank.comnih.gov Characterizing these metabolites and understanding their distribution in biological matrices is important for comprehending this compound's pharmacokinetics and potential mechanisms of action or toxicity. drugbank.comnih.gov

SPME is a sampling and sample preparation technique that allows for the extraction of analytes from various matrices without the need for large volumes of solvent. researchgate.net When coupled with LC-MS, it provides a sensitive and efficient method for the separation, detection, and identification of this compound and its metabolites. researchgate.netxjtu.edu.cnnih.gov

Research utilizing SPME-LC-MS has been applied to study the metabolic fate of this compound in biological systems, including during in vivo lung perfusion. researchgate.netnih.govfrontiersin.orgnih.gov This approach has enabled the near-real-time determination of this compound levels in tissues and perfusate. researchgate.netnih.govnih.gov

Studies employing biocompatible SPME probes in conjunction with LC-MS have investigated the spatial and temporal distribution of this compound in lung tissue during in vivo lung perfusion in a porcine model. researchgate.netnih.govfrontiersin.orgnih.gov These measurements have revealed a heterogeneous distribution of this compound within different sections of the lung over the course of the perfusion. researchgate.netnih.govnih.gov Specifically, this compound concentrations in lung tissue have been observed to peak at certain time points during perfusion, with variations noted between different lung sections and administered doses. researchgate.net

Beyond quantifying the parent compound, SPME-LC-MS allows for the profiling of other low-molecular-weight compounds in biological samples, providing insights into the cellular metabolic landscape in the presence of this compound. frontiersin.orgnih.gov This can help in understanding the biochemical changes associated with this compound exposure and potentially identifying biomarkers related to its activity or localized effects. frontiersin.orgnih.gov The sensitivity and versatility of SPME-LC-MS make it a suitable tool for monitoring drug levels and exploring the metabolic profile in complex biological environments. researchgate.netfrontiersin.orgnih.gov

Data from SPME-LC-MS studies has provided quantitative measurements of this compound concentrations in biological samples. For instance, in porcine in vivo lung perfusion studies, this compound levels in lung tissue and perfusate were measured using Bio-SPME-LC/MS. researchgate.net

Role of Artificial Intelligence in Drug Resistance Research

Artificial intelligence (AI) is increasingly being applied in cancer research, including the study of drug resistance. mdpi.comresearchgate.net AI models have the potential to analyze large-scale, multi-modal data, including electronic health records and omics data, to forecast medication resistance and provide tailored treatment suggestions. mdpi.com

In the context of this compound resistance, AI can contribute by integrating multi-omics data (genomics, transcriptomics, metabolomics) to more accurately predict drug resistance. mdpi.com AI models can investigate the relationship between molecular profiles and resistance phenotypes. mdpi.com Machine learning algorithms are being leveraged to develop molecular signatures predictive of the efficacy of this compound-based chemotherapy. aacrjournals.org These models aim to identify complex molecular patterns associated with treatment benefit, moving beyond single-gene predictors. aacrjournals.org

AI is also being used to develop frameworks for predicting cancer cell sensitivity to chemotherapies, with a specific application in guiding the precision use of this compound in colon cancer adjuvant therapy. nih.gov By inferring the state of cellular signaling systems from diverse omics data, AI models can predict drug response and help clinicians select optimal regimens, potentially reducing unnecessary toxicity in patients unlikely to benefit from this compound. nih.gov The application of AI in drug resistance research is expected to grow with the introduction of multimodal data fusion and reinforcement learning approaches. mdpi.com

Development of Novel Platinum (IV) Prodrugs

Platinum(IV) prodrugs represent a promising strategy to address some of the limitations of existing platinum(II) drugs like this compound, cisplatin, and carboplatin mdpi.comchimia.ch. These prodrugs are typically more kinetically inert than their platinum(II) counterparts, which can potentially lead to reduced premature reactions with biomolecules and thus lower systemic toxicity chimia.chrsc.orgresearchgate.net. The design principle is that these Pt(IV) complexes are reduced intracellularly, particularly in the tumor microenvironment where reducing agents are more abundant, to release the active Pt(II) species and potentially other bioactive axial ligands mdpi.comrsc.orgresearchgate.net.

Research in this area focuses on synthesizing this compound-based Pt(IV) complexes with varying axial ligands to tune their properties, including stability, cellular uptake, reduction potential, and the ability to overcome resistance oup.comfrontiersin.org. The axial ligands can be designed to provide additional therapeutic benefits or targeting capabilities mdpi.comrsc.orgresearchgate.net.

Studies have investigated this compound-derived Pt(IV) complexes with different axial ligands in various in vitro and in vivo models. These studies aim to determine their ability to interfere with DNA, induce apoptosis, affect the cell cycle, and exhibit antitumor activity under different conditions, including hypoxia oup.com. For instance, one study explored four this compound-derived Pt(IV) complexes with varying axial ligands, assessing their cytotoxicity under normoxic and hypoxic conditions in colon carcinoma cell lines oup.com. The results indicated that modifying the axial ligands could improve cytotoxic potency and that these complexes could interfere with plasmid DNA, with this effect being enhanced by co-incubation with a reducing agent oup.com. Some complexes demonstrated the ability to induce apoptosis and cause cell cycle perturbations oup.com.

Novel Pt(IV) prodrugs based on this compound have also been functionalized with other anticancer drugs, such as gemcitabine or capecitabine, in the axial positions mdpi.comresearchgate.net. This approach aims to combine the therapeutic benefits of multiple agents into a single molecule, potentially mitigating side effects and overcoming drug resistance mechanisms observed with single-drug treatments mdpi.com. Studies on such prodrugs have shown their ability to dissociate into their constituents within cancer cells, promote cell death, and induce apoptosis and cell cycle blockade in colorectal cancer cell models mdpi.comresearchgate.net. For example, a complex bearing gemcitabine in the axial position demonstrated significant activity against the HCT116 colorectal cancer cell line with a low IC50 value mdpi.comresearchgate.net.

Furthermore, the encapsulation of these Pt(IV) complexes in biocompatible nanoparticles is being explored to improve their delivery and retention of pharmacological properties mdpi.comtandfonline.com. This nanoformulation strategy can potentially enhance blood circulation stability and improve antitumor capacity tandfonline.com.

Data from in vitro studies comparing the cytotoxicity of this compound and novel Pt(IV) prodrugs in cancer cell lines provide insights into their potential efficacy. For instance, in one study using HCT116 colorectal cancer cells, the IC50 values for this compound and two novel Pt(IV) prodrugs (PTC and PTG) were reported after 72 hours of treatment mdpi.com.

This table illustrates that the PTG complex, functionalized with gemcitabine, exhibited significantly higher cytotoxicity in this specific cell line compared to this compound and the PTC complex mdpi.com.

CRISPR Screening for Drug Resistance Genes

Understanding the molecular mechanisms underlying this compound resistance is crucial for developing strategies to overcome it. CRISPR/Cas9 screening technology has emerged as a powerful tool for systematically identifying genes that contribute to drug resistance in cancer cells frontiersin.orgmdpi.com. By performing genome-wide or targeted CRISPR knockout or activation screens, researchers can pinpoint genes whose alteration affects cellular sensitivity to this compound frontiersin.orgmdpi.combiorxiv.orgbiorxiv.orgresearchgate.net.

Genome-wide CRISPR/Cas9 knockout screens have been conducted in colorectal cancer cell lines to identify genes that, when knocked out, confer resistance to this compound frontiersin.orgbiorxiv.orgbiorxiv.orgresearchgate.net. These screens involve treating a pool of cells with guide RNAs (sgRNAs) targeting thousands of genes with this compound and then identifying sgRNAs that are enriched in the surviving cell population frontiersin.orgbiorxiv.org. Enrichment of sgRNAs targeting a specific gene suggests that the loss of that gene's function leads to this compound resistance frontiersin.orgbiorxiv.org.

One study using genome-wide CRISPR/Cas9 library knockdown screening in colorectal cancer cells identified mitochondrial elongation factor 2 (MIEF2) as a top candidate gene associated with this compound resistance frontiersin.orgnih.govresearchgate.net. This compound-resistant cell lines and organoids showed low expression of MIEF2 frontiersin.orgnih.gov. Reduced MIEF2 expression was found to potentially enhance resistance by affecting mitochondrial stability and inhibiting apoptosis through decreased cytochrome C release frontiersin.orgnih.gov. This suggests MIEF2 could serve as a biomarker for this compound responsiveness and a potential therapeutic target frontiersin.orgnih.gov.

Another genome-wide CRISPR activation and knockout screen in colorectal cancer cell lines identified the amino acid transporter SLC43A1 (which encodes the protein L-type amino acid transporter 3, LAT3) as a major determinant of this compound sensitivity biorxiv.orgbiorxiv.orgresearchgate.net. Knockout of SLC43A1 conferred resistance, while activation increased sensitivity biorxiv.orgbiorxiv.orgresearchgate.net. Further analysis indicated that higher LAT3 levels correlated with increased intracellular this compound levels and subsequent DNA damage, suggesting LAT3 influences this compound uptake biorxiv.orgresearchgate.net.

CRISPR screening has also been applied to identify regulators of sensitivity to platinum drugs, including this compound and cisplatin, in pancreatic cancer cell lines mdpi.com. A screen using different sgRNA libraries identified numerous candidate genes whose knockout altered sensitivity mdpi.com. Among these, several genes previously linked to platinum sensitivity were confirmed, and many novel potential regulators were identified mdpi.com. Some genes, such as BRIP1, ERCC4, FANCD2, FANCG, FANCI, MAD2L2, and NPEPPS, were found to regulate sensitivity to both this compound and cisplatin mdpi.com. Notably, NPEPPS was identified as a platinum sensitivity regulator for the first time in this study mdpi.com.

These CRISPR-based studies provide valuable insights into the complex genetic landscape of this compound resistance, identifying potential biomarkers and therapeutic targets for improving treatment outcomes.