Abiraterone

Cytochrome P450 17A1 (CYP17A1) Inhibition by Abiraterone

Downstream Molecular Effects of this compound on Hormone Production

Androgen Receptor Signaling Modulation by Abiraterone

This compound's principal pharmacodynamic action is the inhibition of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme patsnap.comscispace.comnih.govoup.com. CYP17A1 is essential for the synthesis of androgens, including testosterone, in the adrenal glands, testes, and prostate tumor tissues patsnap.comoup.comfda.gov. This compound functions as a selective and irreversible inhibitor of this enzyme, binding to its heme iron and thereby blocking its catalytic activity patsnap.comscispace.comnih.govoup.comfda.govnih.gov. This inhibition prevents the conversion of pregnenolone and progesterone into 17α-hydroxy derivatives and subsequently blocks the formation of dehydroepiandrosterone (DHEA) and androstenedione, the precursors to testosterone patsnap.comoup.com.

The resultant significant reduction in androgen levels is central to this compound's modulation of androgen receptor (AR) signaling patsnap.comscispace.com. Prostate cancer cells typically rely on androgens to bind to AR, activating downstream pathways that promote cell proliferation and inhibit apoptosis patsnap.combioscientifica.com. By diminishing the availability of these ligands, this compound effectively decreases AR activation, thereby limiting the pro-growth signals within cancer cells patsnap.com. This mechanism is particularly crucial in castration-resistant prostate cancer (CRPC), where tumors often develop mechanisms to sustain AR signaling despite low circulating testosterone levels, including intratumoral androgen synthesis fda.govbioscientifica.com. This compound's ability to inhibit androgen production at multiple sites helps to overcome this resistance nih.govoup.comfda.gov.

However, AR signaling can persist or adapt in the presence of this compound through various mechanisms, such as AR gene amplification, mutations leading to increased AR expression or ligand-independent activation, or the emergence of AR splice variants like AR-V7 bioscientifica.commdpi.comoncotarget.comaacrjournals.org. Some AR mutations, such as AR-T877A, can even lead to resistance by allowing cells to be activated by other steroids, like progesterone, whose levels may increase due to CYP17A1 inhibition oncotarget.com.

Cellular and Molecular Responses to this compound Treatment

This compound treatment elicits a range of cellular and molecular responses that contribute to its antitumor activity.

Cell Growth and Proliferation: this compound demonstrably attenuates cell growth. In androgen receptor (AR)-positive LNCaP cells, this compound treatment significantly decreased cell growth, alongside reductions in AR expression and activity spandidos-publications.com. Similarly, AR-negative PC-3 cells exhibited comparable reductions in cellular proliferation when treated with this compound, suggesting effects beyond direct AR blockade spandidos-publications.com. For instance, PC-3 cells treated with 30 μM this compound for 120 hours showed reduced proliferation spandidos-publications.com. Furthermore, this compound's modulation of the osteoblast secretome led to reduced cancer cell proliferation in AR-dependent C4-2B cells (p = 0.022) and a significant reduction in AR activation (p = 0.017) nih.gov.

Apoptosis and Molecular Pathway Modulation: this compound can induce apoptosis and modulate apoptotic pathways, evidenced by changes in key proteins such as p21, caspase-3, survivin, and transforming growth factor β (TGFβ) spandidos-publications.com. Some studies indicate that this compound may downregulate the anti-apoptotic protein BCL2 and upregulate the pro-apoptotic protein BAX, thereby activating apoptosis pathways researchgate.net.

Gene Expression and Signaling: this compound treatment can induce global gene expression changes nih.gov. It has been observed to increase intracellular cAMP levels and induce kinase activity, leading to the phosphorylation of CREB1 (pCREB1) nih.govaacrjournals.org. This upregulation of pCREB1 is critical for controlling global gene expression and has been implicated in the development of this compound resistance, potentially by augmenting the function of the CBP/p300 complex nih.govaacrjournals.org.

Metabolite Activity: A metabolite of this compound, 3-keto-5α-abiraterone, shares structural similarities with androgens and can activate pro-cancer pathways by tricking androgen receptors, potentially fueling cancer cell growth clevelandclinic.org.

Data Tables

Table 1: Summary of this compound's Mechanism of CYP17A1 Inhibition

Table 2: Cellular and Molecular Responses to this compound Treatment (Examples)

Prodrug Conversion of Abiraterone Acetate to this compound

Following oral administration, this compound acetate is rapidly and extensively converted to this compound. europa.eumdpi.com This conversion is a hydrolysis reaction, catalyzed by esterases, though the specific esterases involved have not been fully identified. mdpi.comdrugbank.comnih.gov This process occurs pre-systemically, meaning it largely takes place before the drug enters the main circulation. mdpi.com In clinical studies, plasma concentrations of the prodrug, this compound acetate, are typically undetectable in the vast majority of samples. drugbank.com The rapid hydrolysis in the intestinal environment can lead to the generation of this compound concentrations that exceed its normal solubility, a phenomenon known as intestinal supersaturation, which creates a strong driving force for its absorption. nih.gov

Hepatic Metabolism of this compound and its Metabolites

This compound undergoes extensive metabolism, primarily in the liver. europa.eu The biotransformation pathways include sulfation, hydroxylation, and oxidation. europa.eu The cytochrome P450 enzyme system, particularly CYP3A4, plays a significant role in its metabolism. nih.govcancercareontario.ca

Several key metabolites of this compound have been identified, which result from its complex metabolic pathways.

Δ4-Abiraterone (D4A): This metabolite is formed from this compound through the action of the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). prostatecancertopics.comnih.gov D4A is considered a more potent antitumor agent than this compound itself. prostatecancertopics.comaacrjournals.org

5α-Abiraterone: Δ4-abiraterone can be further metabolized by 5α-reductase to form 3-keto-5α-abiraterone, also known as 5α-abiraterone. wikipedia.orgoaepublish.com This metabolite has been found to have androgenic activity, potentially counteracting the therapeutic effect of this compound. wikipedia.org

This compound Sulfate and N-oxide this compound Sulfate: These are two major circulating, but pharmacologically inactive, metabolites found in human plasma. drugbank.comnih.gov Together, they account for approximately 86% of the drug's exposure. drugbank.com The formation of this compound sulfate involves the SULT2A1 enzyme, while N-oxide this compound sulfate formation involves both CYP3A4 and SULT2A1. drugbank.comnih.gov

Table 1: Key Metabolites of this compound

The biotransformation of this compound into its various metabolites is a multi-step process involving several key enzymes.

3β-hydroxysteroid dehydrogenase (3βHSD): This enzyme is responsible for the initial conversion of this compound to Δ4-abiraterone (D4A). prostatecancertopics.comresearchgate.net This conversion is significant as D4A exhibits more potent anti-cancer properties than the parent drug. prostatecancertopics.com

5α-reductase: This enzyme acts on D4A, converting it to 5α-reduced metabolites, including the androgenic 3-keto-5α-abiraterone. wikipedia.orgoaepublish.com The irreversible nature of this steroid 5α-reduction means that once formed, these 5α-reduced metabolites are not converted back to this compound or D4A. prostatecancertopics.com

Other Enzymes: Cytochrome P450 enzymes, particularly CYP3A4, and sulfotransferase enzymes like SULT2A1 are crucial for the formation of the major inactive circulating metabolites, this compound sulfate and N-oxide this compound sulfate. drugbank.comnih.gov

Influence of Physiologic Factors on this compound Pharmacokinetics

The pharmacokinetics of this compound can be influenced by various physiologic factors. One area of research has been the effect of long-term administration. A study on the long-term pharmacokinetics of this compound acetate found that individual drug concentrations remained relatively constant over a period of up to 120 days, suggesting no significant changes with repeated administration. mdpi.comnih.gov This study also noted a positive correlation between patient age and this compound concentration, with older patients showing higher drug levels. mdpi.comnih.gov Long-term exposure to this compound and its metabolite D4A has been shown to lead to an increase in the expression and enzymatic activity of 5α-reductase, which could enhance the conversion of D4A to its androgenic 5α-reduced metabolites. nih.gov

In Vitro Models for Abiraterone Research (e.g., Cell Lines)

In vitro studies utilizing diverse cancer cell lines have provided foundational insights into this compound's direct cellular effects and its mechanism of action. These models have been instrumental in characterizing this compound's cytotoxic and cytostatic properties, as well as exploring its impact on specific signaling pathways.

Adrenocortical Carcinoma (ACC) Cell Lines: this compound acetate (AA) has shown concentration-dependent effects on ACC cell lines. In the NCI-H295R cell line, AA treatment led to a reduction in cell viability, with reported decreases in cell number of 22% after two days of treatment with 200 nM AA, increasing to 47% after four days and 62% after six days oup.com. In contrast, the SW13 ACC cell line exhibited no significant change in viability when exposed to this compound oup.com. These findings suggest that the antiproliferative effects of this compound in ACC may be cell-line specific and potentially linked to specific molecular characteristics, such as the expression of the progesterone receptor (PgR), which has been implicated in mediating this compound's cytotoxic effects oup.comnih.gov.

Prostate Cancer Cell Lines: this compound has been evaluated in various prostate cancer cell lines, including androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) models. Studies have shown that this compound and its acetate prodrug can reduce the viability of these cell lines compared to control treatments nih.gov. Specifically, in the 22Rv1 cell line, a prostate cancer model expressing PSMA, the CC50 (concentration causing 50% inhibition of cell growth) for an this compound conjugate (PSMA-Abi) was reported as 8.2 ± 3.1 μM, which was notably lower than that of this compound acetate (AbiAc) at 22.7 ± 3.3 μM, indicating enhanced cytotoxic potential for the conjugate in this model mdpi.com.

Breast Cancer Cell Lines: In the context of breast cancer, this compound has been investigated in models of triple-negative breast cancer (TNBC) that express the androgen receptor (AR), such as the MDA-MB-453 cell line aacrjournals.org. Furthermore, studies have explored this compound's activity in estrogen receptor-positive (ER+) breast cancer cell lines, including MCF7, HCC1428, and SUM44. These investigations suggest that this compound's role in ER+ breast cancer may be context-dependent, potentially influenced by prior hormone therapy and the presence of ESR1 mutations mdpi.com.

Other Cancer Cell Lines: this compound acetate has also been examined in colon cancer cell lines, where it demonstrated an inhibitory effect on tumor growth in vitro, with susceptibility noted in 59% of tumor cells at 50 μL and up to 67% at 300 μL researchgate.net.

Table 1: this compound Efficacy in Cancer Cell Lines

In Vivo Models for this compound Research (e.g., Xenograft Models, Patient-Derived Xenografts)

Preclinical in vivo studies, employing xenograft and patient-derived xenograft (PDX) models, have further validated this compound's anti-tumorigenic potential. These models allow for the assessment of this compound's efficacy in a more complex biological environment, including its impact on tumor growth, progression, and survival.

Adrenocortical Carcinoma (ACC) Xenografts: In immunodeficient mice bearing NCI-H295R cell line xenografts, this compound acetate (AA) demonstrated an ability to inhibit tumor growth. Treatment with AA led to a tumor volume inhibition (TVI) of 38% at day 36 post-treatment initiation (P = 0.07) and maintained a TVI of 34% by day 61 (P = 0.009) oup.com.

Prostate Cancer Xenografts and PDXs: this compound has been extensively studied in various prostate cancer xenograft and PDX models. In 22Rv1 xenografts, this compound acetate (AbiAc) achieved a 78% tumor growth inhibition (TGI), while a PSMA-targeted this compound conjugate (PSMA-Abi) showed a TGI of 65% mdpi.com. Studies utilizing castration-resistant prostate cancer (CRPC) patient-derived xenografts (PDXs) have revealed heterogeneity in response to AA. For instance, LuCaP 136CR PDXs exhibited an "ultraresponsive" phenotype with significant tumor progression inhibition and improved median survival (21.6 weeks vs. 6.8 weeks, P<0.0001), whereas LuCaP 35CR PDXs showed minimal tumor inhibition and no survival benefit aacrjournals.orgresearchgate.net. LuCaP 77CR and LuCaP 96CR PDXs demonstrated intermediate responses with modest tumor inhibition and survival benefits aacrjournals.orgresearchgate.net. In the LAPC-4 xenograft model, this compound was found to be less efficacious compared to a novel analog nih.gov. Furthermore, combination studies in CWR22Rv1 xenografts showed that this compound acetate, when combined with niclosamide, synergistically inhibited tumor size and weight compared to this compound alone oncotarget.com. In triple-negative breast cancer (TNBC) models, orthotopic xenograft experiments confirmed the efficacy of this compound acetate in combination with a Chk1 inhibitor aacrjournals.org.

Table 2: this compound Efficacy in Xenograft and PDX Models

This compound Efficacy in Diverse Cancer Models (e.g., Adrenocortical Carcinoma, Breast Cancer, Ovarian Cancer)

The translational potential of this compound has been explored in various cancer types beyond prostate cancer, leveraging its mechanism of inhibiting androgen biosynthesis, a pathway relevant in several hormone-sensitive malignancies.

Adrenocortical Carcinoma (ACC): Preclinical investigations have established this compound's efficacy in ACC models. In vitro, this compound acetate reduced cell viability and hormone secretion in ACC cell lines and primary cultures, with its cytotoxic effect potentially mediated by progesterone receptor activity oup.comnih.govresearchgate.net. In vivo, this compound demonstrated anti-tumor activity in NCI-H295R xenografts, inhibiting tumor growth oup.comnih.govresearchgate.net.

Ovarian Cancer: The androgen receptor (AR) is expressed in a significant proportion of epithelial ovarian cancer (EOC) cases, providing a rationale for exploring AR-targeted therapies. While preclinical studies using enzalutamide, another AR inhibitor, showed reduced EOC xenograft growth, clinical trials with this compound acetate in recurrent EOC (CORAL trial) yielded rare responses. However, a subset of patients did achieve sustained clinical benefit, indicating that AR-targeting strategies may warrant further investigation in specific ovarian cancer subtypes nih.govtargetedonc.comresearchgate.net.

Table 3: this compound Efficacy in Different Cancer Types

Compound List:

this compound

this compound acetate (AA)

PSMA-Abi

AbiAc

Enzalutamide

Bicalutamide

Seviteronel

Mitotane

Cabazitaxel

Niclosamide

Onvansertib

Galeterone

D4A (Δ4-abiraterone)

CB7598

Enobosarm

Prednisone

Q. How to resolve discrepancies between preclinical efficacy and clinical trial outcomes for this compound-based therapies?

• Answer :
• Tumor heterogeneity : Use multi-region sequencing in PDX models to identify resistant subclones.
• Dosing : Compare preclinical doses (mg/kg) to human equivalent doses (HED) using FDA guidelines.
• Biomarker discordance : Validate surrogate endpoints (e.g., PSA) with tissue-based AR-V7 expression .