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Review
. 2024 Aug 6;16(16):2777.
doi: 10.3390/cancers16162777.

Synergistic Strategies for Castration-Resistant Prostate Cancer: Targeting AR-V7, Exploring Natural Compounds, and Optimizing FDA-Approved Therapies

Muntajin Rahman  1 , Khadija Akter  2 , Kazi Rejvee Ahmed  1 , Md Maharub Hossain Fahim  1 , Nahida Aktary  1 , Moon Nyeo Park  1 , Sang-Won Shin  3 , Bonglee Kim  1   2
Affiliations
Review

Synergistic Strategies for Castration-Resistant Prostate Cancer: Targeting AR-V7, Exploring Natural Compounds, and Optimizing FDA-Approved Therapies

Muntajin Rahman et al. Cancers (Basel). .

Abstract

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge due to its resistance to standard androgen deprivation therapy (ADT). The emergence of androgen receptor splice variant 7 (AR-V7) has been implicated in CRPC progression, contributing to treatment resistance. Current treatments, including first-generation chemotherapy, androgen receptor blockers, radiation therapy, immune therapy, and PARP inhibitors, often come with substantial side effects and limited efficacy. Natural compounds, particularly those derived from herbal medicine, have garnered increasing interest as adjunctive therapeutic agents against CRPC. This review explores the role of AR-V7 in CRPC and highlights the promising benefits of natural compounds as complementary treatments to conventional drugs in reducing CRPC and overcoming therapeutic resistance. We delve into the mechanisms of action underlying the anti-CRPC effects of natural compounds, showcasing their potential to enhance therapeutic outcomes while mitigating the side effects associated with conventional therapies. The exploration of natural compounds offers promising avenues for developing novel treatment strategies that enhance therapeutic outcomes and reduce the adverse effects of conventional CRPC therapies. These compounds provide a safer, more effective approach to managing CRPC, representing a significant advancement in improving patient care.

Keywords: androgen receptor blockers; androgen receptor splice variant 7; castration-resistant prostate cancer; herbal medicine; natural compounds.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Structural and Functional Insights into the Androgen Receptor and Its Role in CRPC. The androgen receptor (AR) gene, located on the X chromosome at Xq11-12, encodes the AR-V7 protein, which includes four distinct domains: N-terminal domain (NTD), DNA-binding domain (DBD), hinge region, and ligand binding domains (LBD). Activation of the AR by androgens such as testosterone and dihydrotestosterone (DHT) initiates a cascade of events that promote prostate cancer cell proliferation. Aldo-keto reductase family 1 member C3 (AKR1C3) is overexpressed in castration-resistant prostate cancer (CRPC) and is crucial for the synthesis of DHT from weak androgens, contributing to the persistence of AR signaling in low-androgen environments. Furthermore, testosterone is converted to the more potent androgen DHT through the action of 5α reductase, further fueling the growth of CRPC cells despite androgen deprivation therapy.
Figure 2
Figure 2
Overview of AR-V7 and AR splice variants. The androgen receptor (AR) gene, located on the X chromosome, comprises eight exons that encode four primary domains: The N-terminal domain (NTD), DNA-binding domain (DBD), hinge region (H), and ligand-binding domain (LBD). The AR gene can undergo alternative splicing, producing several splice variants, each with distinct structures and functions. In the full-length androgen receptor (AR-FL), exons 1–8 encode the complete set of domains. However, alternative splicing can involve cryptic exons (CE1-4) and exon 9, generating a unique sequence (U) not found in AR-FL. AR-V7, also known as AR3, is a significant splice variant that terminates at the end of exon 3, lacking the LBD, and includes 16 unique amino acids from cryptic exon 3 (CE3). This modification results in AR-V7’s constitutive activity, allowing it to activate AR signaling pathways without the need for androgen binding. Additionally, other constitutively active AR splice variants, such as ARv567es, AR-V3, and AR-V4, are described. Each variant arises from different exon combinations, producing unique open reading frames (ORFs) that encode their respective receptor proteins.
Figure 3
Figure 3
Mechanism of action of first-generation chemotherapy (Docetaxel, cabazitaxel) in treating CRPC. Docetaxel and cabazitaxel, both taxane-based chemotherapeutic drugs, exert their anticancer effects primarily by targeting microtubules. These drugs bind to β-tubulin, stabilizing microtubules and preventing their proper assembly. This disruption inhibits the G2-M phase transition of the cell cycle, leading to cell cycle arrest and apoptosis. Additionally, taxanes inhibit androgen receptor (AR) transcriptional activity by blocking FOXO1-mediated AR function, which is crucial in treating castration-resistant prostate cancer (CRPC). By obstructing AR signaling, taxanes effectively disrupt the growth and survival mechanisms of CRPC cells. Taxanes also promote apoptosis through the activation of pro-apoptotic proteins such as BAK and BAX while inhibiting anti-apoptotic proteins like BCL-2 and BCL-XL. This dual action triggers the intrinsic apoptotic pathway, characterized by the release of cytochrome c from mitochondria, culminating in cell death. Overall, the combination of microtubule stabilization, inhibition of AR signaling, and promotion of apoptosis underscores the therapeutic efficacy of docetaxel and cabazitaxel in managing CRPC.
Figure 4
Figure 4
Mechanism of action of androgen receptor blockers (Apalutamide, Darolutamide, and Enzalutamide) in treating CRPC. Enzalutamide, Apalutamide, and Darolutamide are androgen receptor (AR) antagonists that effectively inhibit the androgen signaling pathway, crucial for the progression of castration-resistant prostate cancer (CRPC). Enzalutamide binds to the AR, preventing testosterone from attaching to the receptor. This inhibition blocks the translocation of the AR into the cell nucleus, thereby preventing the activation of AR target genes that promote cancer cell growth. In addition to direct AR antagonism, Abiraterone acetate targets androgen synthesis. It inhibits the enzyme 17α-hydroxylase and C17,20-lyase, which are essential for androgen production, by blocking their activity on the CYP-17. This action significantly reduces the levels of testosterone and other androgens, preventing their binding to the AR. Apalutamide and Darolutamide function similarly to Enzalutamide by binding to the AR and preventing its activation by testosterone. This inhibition blocks AR-mediated transcriptional activity, thereby hindering the growth of CRPC cells. By disrupting the androgen signaling pathway through these different mechanisms, these treatments aim to reduce AR activity and slow the progression of CRPC.
Figure 5
Figure 5
FDA-Approved Treatments for Castration-Resistant Prostate Cancer (CRPC). Radium-223 and Lutetium-177 are radiopharmaceuticals used in the treatment of CRPC. Radium-223 emits high-energy alpha particles, while Lutetium-177 emits beta particles. These particles directly damage the DNA of cancer cells, leading to cell death. Both treatments specifically target bone metastases, a common complication in CRPC, effectively reducing tumor burden. The precision of these therapies helps minimize damage to surrounding healthy tissues, providing a focused approach to treat metastatic bone lesions. Pembrolizumab, an immune checkpoint inhibitor, is a key immunotherapy approved for CRPC. It binds to PD-1 receptors on T cells, blocking the interaction between PD-1 on T cells and PD-L1 on tumor cells. This blockade lifts the immune suppression exerted by the tumor, thereby activating the immune system to recognize and attack cancer cells. The immune response is initiated by the detection of neoantigens presented on major histocompatibility complexes (MHC) by tumor cells. This mechanism enhances the body’s natural defense against cancer by overcoming one of the major immune evasion strategies employed by tumors.
Figure 6
Figure 6
Mechanism of action of PARP inhibitors (Olaparib, Rucaparib, and Niraparib) in treating castration-resistant prostate cancer (CRPC). PARP inhibitors such as Olaparib, Rucaparib, and Niraparib block the PARP enzyme, which is crucial for repairing single-strand DNA breaks. Inhibition of PARP leads to the persistence of single-strand breaks, which during DNA replication, result in double-strand breaks. Cells with BRCA1 or BRCA2 mutations exhibit homologous recombination deficiency (HRD). These cells are unable to efficiently repair double-strand breaks through the homologous recombination pathway. The accumulation of unrepaired double-strand breaks in HRD cells triggers cell death, effectively targeting cancer cells harboring BRCA mutations. This targeted approach exploits the inherent weaknesses in the DNA repair mechanisms of CRPC cells, providing a potent and specific strategy to combat this challenging form of cancer.
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