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

3.1. The Crucial Strategies That Can Target AR-V7 for the Treatment of CRPC

CRPC is resistant to androgen deprivation therapy due to AR-V7, requiring novel techniques to target AR-V7 directly or indirectly to improve treatment results [30]. Modern tactics and ongoing investigations in this quickly evolving field are discussed in this discussion of AR-V7 strategies.

1. AR-V7 Resistance: Two antisense oligonucleotides (AONs) were created to target AR pre-mRNA splicing enhancers, restoring sensitivity to androgen deprivation and inducing apoptosis in CRPC cell lines [31]. AKR1C3 and AR-V7 interact in prostate rebiopsy tissues, preventing degradation and repressing B4GALT1, a prostate cancer tumor suppressor gene essential for CRPC cell proliferation post-androgen deprivation [32].

2. Targeting AR-V7 Translation/Transcription: AR-FL binds to ARBS2, an AR intron 2 enhancer, to inhibit chromatin. These negative autoregulatory mechanisms of ADT enhance AR-FL and AR-V mRNA simultaneously. The AR-FL protein boosts AR-FL and AR-V transcripts after ADT [33]. A tiny molecule SC912 interacts with full-length AR and AR-V7 via its N-terminal domain. Pan-AR targeting uses AR-NTD amino acids 507–531. SC912 prevented AR-V7 nuclear localization, DNA binding, and transcription. SC912 stopped AR-V7-positive CRPC cell growth, cell-cycle arrest, and death. SC912 inhibited AR signaling and CRPC xenograft development in AR-V7-expressing cells. These findings suggested SC912 could treat CRPC [34].

3. Combination Therapies: New targeted, immunological, AR-targeting, and chemotherapy. Metastatic Castration-Resistant Prostate Cancer Treatment) and AFFINITY (Cabazitaxel/Prednisone Alone or With Custirsen for 2nd-line Prostate Cancer Chemotherapy). Reactivating AR activity is another docetaxel resistance mechanism. A gene mutation that makes AR translocation independent of microtubule control can produce docetaxel resistance. Drug interactions with cytotoxic treatment can cause fatal neutropenic enterocolitis [35].

4. AR-V7-Targeted Immunotherapy: AR-V7-Targeted Immunotherapy (MVI-118) is a DNA vaccine for metastatic prostate cancer, promoting a CD8+T cell-mediated immune response against AR-overexpressing cancer cells. Genomic profiling can detect genetic changes and molecular subtypes, potentially predicting treatment response. Next-generation sequencing technologies can also reveal immune response landscapes and immunotherapy-predictive biomarkers in tumor microenvironments [5,36].

5. Epigenetic Modulators: Emerging evidence links non-coding RNAs to CRPC development and treatment resistance, while AR-epigenetic pathways are specifically engaged in PC carcinogenesis [7]. Histone regulators including LSD1 and EZH2 can have a significant impact on AR expression and help CRPC re-programme AR activation. The expression of EZH2 and BRD4, which stimulates regulators and engages with acetylated histones to coactivate AR. Epigenetic alterations help PCa cells respond to AR signaling suppression. Recent research conducted that EZH2 can make CRPC tumors resistant to DNA-damaging therapies

6. Proteolysis-Targeting Chimeras (PROTACs): In recent years, targeting AR protein for breakdown by AR-targeted proteolysis targeting chimeras (PROTACs) or small-molecule degraders has become an interesting and potentially useful way to treat metastatic CRPC (mCRPC) [37]. The way AR expression inhibitor functions are different from how PROTAC targets AR protein. AR expression inhibitor uses antisense oligonucleotides to target AR mRNA by binding the complementary region of AR mRNA, which significantly lowers mRNA production [38].

3.2. Certain Processes Supporting CRPC Evolution Similar to AR-V7

Various mechanisms confer resistance to next-generation AR-directed therapies, such as activation of canonical AR-signaling through AR amplification, feedback pathway activation (e.g., AKT/mTOR/PI3K), and AR mutations or substitutions (e.g., AR splice variants) [39].

Epigenetic modifications also play a significant role in cancer progression. These changes can provide insights into early cancer detection, prognosis, and risk assessment. Epigenetics involves heritable variations in gene expression without altering the DNA sequence [40]. mRNA acts as a link between genetic information and protein synthesis, making it crucial in converting genotypes into phenotypes [41]. Epigenetic changes can occur in both enhancer regulatory and promoter regions around the transcription start point, impacting transcription, DNA repair, and replication through modifications like phosphorylation, acetylation, methylation, and ubiquitination. DNA methylation has been the most studied regulatory method, but histone protein modifications are now recognized as significant chemical components of epigenetic up-regulation. Research in Clonal Hematopoiesis of Indeterminate Potential (CHIP) has shown that most mutations occur in pre-leukemic driver genes, affecting other illnesses beyond hematologic malignancies [42].

Epigenetic modifications, similar to AR-V7, contribute to CRPC development. DNA methylation and histone modifications are the most common epigenetic changes in prostate cancer, affecting gene expression and promoting cancer progression [43]. Key epigenetic modifications include RNA methylation, DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, which regulate solid tumors and hematologic malignancies [44].

Given these insights, AR-V7 is gaining attention as a resistance mechanism to anti-androgen receptor therapies for CRPC and as a potential predictive marker for these therapies. Developing next-generation drugs targeting AR-V7 signaling is critically necessary [45].

3.3. Clinical Intervention Linked to AR-V7 in the Development of CRPC

5.1. First-Generation Chemotherapy for Prostate Cancer

The development and FDA approval of antiandrogen therapies have significantly transformed the treatment landscape for prostate cancer, particularly in managing castration-resistant prostate cancer (CRPC). Over the past decade, advancements in understanding the molecular mechanisms of CRPC have led to significant improvements in its treatment [68]. First-generation therapies for prostate cancer comprise bicalutamide, mitoxantrone, cabazitaxel, and docetaxel. This section highlights the classification of chemotherapeutic drug and mechanism of action in the treatment of Prostate cancer, as detailed in Table 2.

5.2. Androgen Receptor Blockers

Androgen suppression therapy, also known as novel hormone therapy, targets the androgen signaling pathway to reduce androgen levels [94]. Overexpression of androgens drives the progression of both metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) [95]. Antiandrogens primarily inhibit androgen receptor (AR) signaling by preventing its nuclear translocation and subsequent activation of AR-targeted genes. The FDA has approved several drugs, including enzalutamide, apalutamide, and darolutamide. Figure 4 illustrates the Mechanism of action of androgen receptor blockers (Apalutamide, Darolutamide, and Enzalutamide) in treating CRPC.

5.3. Androgen Biosynthesis Inhibitors

Instead of primarily blocking the androgen receptor, another method of inhibiting androgen signaling is to target the upstream synthesis of androgens. The cytochrome P450 17α-hydroxylase-17,20-lyase (CYP17A1) enzyme is essential for the generation of androgens in the testes, adrenal glands, and malignancies. The testosterone production pathway is interfered with by blocking CYP17A1, which lowers androgen levels and stops the formation of dihydrotestosterone (DHT).

5.4. Radiation Therapy

Radiation therapy is a common treatment for early stage localized prostate cancer, targeting locally advanced cancers and reducing the risk of metastasis. Despite significant progress, radiation therapy’s limited therapeutic window results in many patients experiencing cancer recurrence. Increasing radiation doses can damage healthy tissues, causing adverse effects. Emerging techniques like proton and carbon ion therapy aim to target tumor cells more precisely while minimizing harm to nearby healthy cells [111]. Approximately 60–70% of patients experience tumor recurrence (10–40%) after radical prostatectomy, with side effects such as radiation proctitis being avoidable through accurate patient positioning and thorough setup verification [112].

5.5. Immunotherapy

Immunotherapies enhance the patient’s immune system to fight cancer cells. The FDA has approved three immunotherapies for CRPC: an immune-cell-based vaccine and two immune checkpoint inhibitors (ICI) [73]. Prostate cancer cells express proteins like PSA and prostatic acid phosphatase (PAP), potential targets for antigen-based vaccines [117].

5.6. PARP Inhibitors

Four PARP inhibitors approved by both the FDA and the European Medicines Agency (EMA) are leading the way in extended treatment approaches using targeted therapies for specific cases of prostate cancer. These drugs include olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) [70,134,135]. They are indicated for patients with prostate cancer that has spread and is no longer responsive to hormone therapy, known as castration-resistant disease. Eligibility for these inhibitors requires specific genetic abnormalities that impair cells’ ability to repair DNA damage. In treating metastatic prostate cancer, conventional therapies inhibit hormones to halt their support for cancer growth and spread. However, PARP inhibitors function differently by targeting the PARP protein, crucial for repairing single-strand DNA breaks (SSBs) [136]. Each of these inhibitors varies in their specificity for different PARP proteins. Notably, rucaparib exhibits the least selectivity, binding not only to PARP1 but also to other PARP proteins and additional targets such as hexose-6-phosphate dehydrogenase, leading to diverse effects. Despite their promise, limitations exist in current treatments, underscoring the need for alternative therapies or natural compounds. Each treatment modality carries specific limitations and side effects, advocating for a combination approach to enhance clinical outcomes while minimizing adverse effects. Ongoing research aims to develop new compounds and therapies that can overcome these limitations, offering more effective and safer options for patients with castration-resistant prostate cancer (CRPC). Figure 6 illustrates the role of PARP inhibitors in the management of CRPC.

7.1. Berberine in Cancer Therapy

Researchers are increasingly focusing on alternative medicines with low toxicity and fewer side effects for preventing and treating prostate cancer. Natural products, including berberine, have shown significant promise as chemotherapeutic agents [156]. Berberine exhibits a wide range of pharmacological activities, such as antimicrobial, anti-inflammatory, and anti-diabetic properties. Recent studies highlight its extensive antitumor activity, including inhibiting cancer cell proliferation, inducing apoptosis, and preventing invasion and migration [156,157]. Berberine specifically decreases the migration and invasion abilities of highly metastatic prostate cancer cells. It downregulates several mesenchymal genes involved in the epithelial–mesenchymal transition (EMT), which is critical for cancer metastasis [158,159]. Notably, higher expressions of BMP7, NODAL, and Snail genes correlate with poorer survival rates in metastatic prostate cancer patients, making them potential therapeutic targets [159]. Additionally, berberine enhances the sensitivity of resistant cancers to chemotherapy and radiotherapy by inhibiting HIF-1α and VEGF expressions, thus increasing radiosensitivity [160]. It also triggers tumor cell apoptosis through the p53-mediated intrinsic apoptotic pathway and elevates reactive oxygen species (ROS) production [161].

In androgen-dependent and castration-resistant prostate cancer (CRPC) cells, berberine suppresses AR transcriptional activity and the expression of AR-regulated genes. It promotes the proteasome-mediated degradation of AR proteins, inhibits the interaction between AR and heat shock protein 90 (Hsp90), and prevents AR nuclear translocation. This results in the degradation of both full-length AR and AR splice variants lacking the ligand-binding domain (ARΔLBDs) [138]. These findings underscore berberine’s potential as a promising treatment for CRPC, warranting further research and development to target AR signaling pathways effectively.

7.2. Curcumin in Cancer Therapy

Curcumin, a bioactive compound from turmeric, exhibits significant anti-cancer properties. It inhibits cancer cell growth and survival, reduces inflammation, prevents invasion, and induces apoptosis in malignant cells [162]. Studies have shown curcumin’s effectiveness against various disorders due to its anti-inflammatory, antioxidant, and antimicrobial properties [163,164].

In prostate cancer (PCa), curcumin interacts with multiple molecular targets, such as mTOR, p53, Ras, PI3K/Akt, and Wnt-β catenin, disrupting cancer growth at various stages. It demonstrates chemopreventive attributes, capable of stopping, reversing, and inhibiting cancer development [165,166]. Animal experiments have shown curcumin’s dose-dependent chemopreventive benefits against PCa [167]. Moreover, curcumin acts as a chemo- and radiosensitizer, enhancing the efficacy of conventional therapies [168].

Curcumin’s safety profile is well-established [169], with clinical research validating its low toxicity and minimal side effects at all dosages [170]. The U.S. Food and Drug Administration (USFDA) has categorized curcumin as Generally Recognized As Safe (GRAS), recommending a daily intake of 8 to 12 g [171]. Curcumin’s anti-tumor properties extend to various cancer types, including prostate cancer [172,173,174]. It inhibits the overexpression of oncogenes and signaling pathways involved in PCa, such as Bcl-2 [175], androgen receptor (AR) signaling, EGFR, HER2, Cyclin D1, COX-2, MMPs, Akt, NF-κB, AP-1, STAT3, MAPK, JAK/STAT, and PI3K/Akt/mTOR. Curcumin has shown efficacy similar to traditional chemotherapy medications in inhibiting the proliferation of androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells [176]. These findings underscore curcumin’s potential as a promising treatment for prostate cancer, warranting further research and development to fully harness its therapeutic benefits [177].

7.3. Cryptotanshinone (CTS)

Cryptotanshinone (CTS), a diterpene quinone from Danshen (Salvia miltiorrhiza Bunge), has shown promise in cancer treatment due to its specific cytotoxicity towards prostate cancer cells, with minimal effects on normal cells. It induces apoptosis and cell cycle arrest in cancer cells, evidenced by upregulating cyclin A1, cyclin B1, and Cdc25c, leading to G2/M phase arrest. Additionally, CTS enhances the sensitivity of drug-resistant prostate cancer cells to apoptosis mediated by Fas and various chemotherapeutic agents, including doxorubicin and cisplatin [178]. CTS is known for its selective inhibition of the STAT3 signaling pathway, without affecting other STAT family proteins. It inhibits the transcriptional activity of the activated androgen receptor (AR) in prostate cancer cells without altering AR mRNA or protein levels. This inhibition is mediated through the suppression of AR target genes, such as NKX3.1, TMPRSS2, and PSA. Furthermore, CTS interferes with the interaction between AR and the histone demethylase LSD1, preventing the demethylation of histone H3 at lysine 9 (H3-K9), thus inhibiting AR-mediated gene activation and prostate cancer growth [179]. Recent studies suggest that the AR-LSD1 interaction is a primary target for CTS-mediated inhibition, highlighting the potential of CTS as a novel therapeutic agent in the treatment of castration-resistant prostate cancer (CRPC). The effects of CTS on the assembly of the AR, JMJD2C, and LSD1 complex on chromatin warrant further investigation to fully understand its therapeutic potential and mechanisms of action [180].

7.4. Epigallocatechin-3-Gallate (EGCG)

Epigallocatechin-3-gallate (EGCG), the primary catechin in green tea, has been extensively studied for its potential anti-cancer properties. Research has demonstrated that EGCG can significantly reduce prostate cancer cell proliferation [181]. Various mechanistic studies have shown that EGCG selectively induces apoptosis and inhibits the proliferation of several cancer cell lines, including DU145, PC-3, and LNCaP, in a dose-dependent manner [182].

Chronic inflammation is a known contributor to tumor development, and EGCG has been shown to modulate inflammatory mediators such as COXs, MMPs, IL-1β, and TNF-α. These inflammatory markers, when overexpressed, often correlate with poorer cancer prognoses. EGCG effectively inhibits these mediators, thus reducing inflammation and potentially curbing cancer progression [183].

In prostate cancer cells, EGCG has demonstrated antiproliferative effects regardless of androgen sensitivity. It induces apoptosis and disrupts the cell cycle, causing a dose-dependent arrest in the G0/G1 phase in both androgen-sensitive and insensitive cells. This arrest is mediated by the induction of cyclin kinase inhibitor WAF1/p21 and an increase in p53 levels in LNCaP cells but not in DU145 cells, which carry mutant p53. This indicates that EGCG can negatively regulate prostate cancer cell growth by affecting mitogenesis and inducing apoptosis in a cell-type-specific manner [184]. Furthermore, EGCG’s regulatory functions extend to intracellular calcium mobilization, crucial for cancer development. High doses of EGCG cause an initial rise in intracellular calcium, interacting directly with plasma membrane proteins and phospholipids. This action is critical in various cell types, including smooth muscle cells and mast cells, where EGCG has been shown to activate calcium influx through different channels [185]. Overall, EGCG’s multifaceted mechanisms of action, including anti-inflammatory effects, cell cycle arrest, and apoptosis induction, highlight its potential as a therapeutic agent in prostate cancer treatment. Further studies and clinical trials are essential to fully understand its efficacy and therapeutic application in cancer management.

7.5. Fisetin

Fisetin, a dietary tetra-hydroxyflavone found in various fruits and vegetables, has shown potential as a chemotherapeutic agent against prostate cancer. Studies reveal that fisetin inhibits several cancer-causing pathways in both in vitro and in vivo models [186]. It demonstrates anti-cancer properties by stabilizing microtubules, reducing cancer cell motility, invasion, and proliferation. In prostate LNCaP cells, fisetin induces G1 phase cell cycle arrest by downregulating cyclins and cyclin-dependent kinases and activates apoptotic pathways [187]. Research on prostate cancer cell lines (LNCaP, DU145, PC-3) has demonstrated fisetin’s effectiveness in reducing tumor growth by competing with AR ligands, lowering AR stability, and enhancing TRAIL-induced apoptosis [188]. Additionally, fisetin decreases the activities of MMP-2 and MMP-9, which are essential for cancer cell invasion and migration [189]. This inhibition occurs through the suppression of the JNK and PI3K/Akt signaling pathways, reducing metastasis potential [188].

Fisetin’s anti-metastatic effects are further supported by its ability to inhibit NF-κB and activator protein 1 (AP1), preventing their nuclear translocation and subsequent binding to the regulatory sequences of MMP-2 and MMP-9 [190]. This action disrupts the extracellular matrix (ECM) breakdown necessary for cancer cell migration. Furthermore, fisetin induces cell cycle arrest in the G1 phase by decreasing CDK2, CDK4, CDK6 activities, and the levels of cyclins D1, D2, and E [188].

At the molecular level, fisetin targets microtubules by binding to β-tubulins, preventing cell proliferation, migration, and invasion, while increasing α-tubulin acetylation. This stabilization of microtubules disrupts mitosis and cell growth in prostate cancer cells [187]. Fisetin also influences Y-box binding protein-1 (YB-1), which regulates EGFR expression and epithelial-to-mesenchymal transition (EMT). By binding to the cold shock domain (CSD) of YB-1, fisetin suppresses YB-1 phosphorylation and AKT, inhibiting EMT [191]. Fisetin demonstrates significant anti-cancer potential by modulating key molecular pathways, inducing apoptosis, and inhibiting cell proliferation and metastasis in prostate cancer cells. Its ability to target multiple pathways highlights its promise as a therapeutic agent in prostate cancer treatment [192].

7.6. Genistein

Genistein, a prominent constituent of soy isoflavones, has demonstrated significant inhibitory effects on CRPC as evidenced by numerous studies. Genistein exerts a broad range of molecular effects, including inflammation inhibition, apoptosis promotion, and regulation of steroid hormone receptors and metabolic pathways [193]. Moreover, androgen deprivation therapy (ADT) may upregulate the PI3K/AKT pathway due to inhibitory feedback loops within the androgen receptor (AR) signaling pathway, and upregulation can occur independently of AR-V7, potentially leading to increased AKT1 expression without direct regulation by AR-FL [194]. The comprehensive understanding of genistein’s molecular mechanisms and its integration with current therapeutic strategies underscores its potential as a valuable agent in treating CRPC. The usage of a particular dosage, the physiological condition of the test organism, and food are likely to have an impact on the effectiveness of genistein in the context of cancer therapy. It is still unclear how and to whom genistein should be given to produce the intended health effects, and how it works at the beginning and end stages of the cancer process. In light of the possibility of cancer, it is also critical to respond to the question of whether genistein-containing supplementation is safe for women. The explanation for how genistein in its nano and micro form could function is another crucial factor. These days, research on phenolic compounds in their nanoscale forms has gained significant importance. Their bioavailability varies in the nano form. Absorption, systemic circulation penetration, and cellular usage are the three fundamental stages that characterize bioavailability. In comparison to macromolecules, the reduction of materials at the nanoscale can result in the creation of novel physical, chemical, and biological properties. It is important to highlight that the literature on the topic being discussed still lacks study [195]. However, the amounts of calcitriol in prostate tissues may be reduced by genistein. In several forms of prostate cancer, androgen deprivation treatment is widely recognized. In order to halt the prostate’s growth, this treatment lowers testosterone levels. Genistein’s capacity to cause apoptosis, suppress important components of cell growth, and alter miRNA expression is proven. Its therapeutic effectiveness has been further boosted by conjugating it with gold nanoparticles and incorporating it into specific liposomes, therefore providing a more selective therapy method. Furthermore, genistein’s extensive significance in managing prostate cancer is highlighted by its potential benefits in reducing the negative effects of hormonal therapy [196]. Prospective research on the use of genistein as an antimetastatic drug was prompted by epidemiologic studies that suggested genistein may have antimetastatic efficacy against PCa in people. Significant proof that genistein can alter the potential for human PCa to spread has been obtained from these investigations. Genistein therapy reduced metastatic load and decreased cell detachment in an orthotopic human PCa model, while leaving the primary tumor size unchanged [197].

7.7. Garcinia Mangostana/α-Mangosteen

Mangosteen (Garcinia mangostana L.) contains xanthones, bioactive substances with significant anticancer properties. Among them, α-mangostin has shown potential due to its ability to inhibit cell proliferation, induce apoptosis, and impede metastasis in prostate cancer cells [198]. Recent studies highlight its effectiveness in promoting androgen receptor (AR) degradation and activating the unfolded protein response pathway, crucial for targeting CRPC (Castration-Resistant Prostate Cancer) [199]. Researchers have found that α-mangostin significantly reduces the viability of prostate cancer cells (PC3 and 22Rv1) by inducing cell cycle arrest through CDK4 inhibition and apoptosis via caspase-3 activation [200]. In vivo studies using an athymic nude mouse model confirmed α-mangostin’s capability to degrade both AR and AR-V7, demonstrating substantial efficacy in reducing cancer growth, especially in CRPC-like conditions. Notably, α-mangostin was the only treatment to show considerable reductions in tumor development, surpassing traditional treatments like bicalutamide. Further investigations revealed that α-mangostin treatment led to decreased expression of genes regulated by AR and AR-V7 in tumor tissues. Despite some discrepancies in AR and AR-V7 expression outcomes between in vitro and in vivo studies, α-mangostin’s promising results warrant more research to fully understand its mechanisms and therapeutic potential against CRPC. These findings position α-mangostin as a valuable candidate for developing new treatments for prostate cancer, particularly in overcoming resistance to conventional therapies [201].

7.8. Ginsenosides

The main pharmacologically active ingredients in ginseng are ginsenosides. These compounds are the primary bioactive constituents responsible for ginseng’s medicinal properties, particularly ginsenoside 20(S)-protopanaxadiol-aglycone. This specific ginsenoside has been demonstrated to suppress androgen receptor (AR) expression and inhibit AR transactivation even under androgen-independent conditions. Research has shown that ginsenoside 20(S)-protopanaxadiol-aglycone effectively inhibits the growth of castration-resistant prostate cancers (CRPC) that express both full-length AR (AR-FL) and AR splice variants (AR-Vs). Additionally, this ginsenoside has been found to either prevent or decelerate the progression of CRPC following androgen deprivation therapy in xenograft models [202]. These findings highlight the potential of ginsenoside 20(S)-protopanaxadiol-aglycone as a therapeutic agent for managing CRPC by targeting both AR-FL and AR-Vs. This dual targeting capability is particularly important, given the role of AR-Vs in promoting treatment resistance and disease progression in CRPC.

7.9. Honokiol

Honokiol, a natural compound extracted from the magnolia tree’s seed cones and bark, has shown significant anticancer properties [203]. In preclinical models and in vitro studies, honokiol has demonstrated its ability to induce apoptosis in cancer cells through multiple signaling pathways, including NF-κB, STAT3, EGFR, and mTOR. It has also displayed favorable pharmacokinetics and bioavailability in animal models, making it a promising candidate for clinical studies [204]. Honokiol targets several molecular pathways involved in cancer progression. It binds effectively to apoptotic factors, chemokines, transcription factors, and kinases, enhancing its therapeutic potential. In the human prostate, honokiol impacts cell cycle regulation and contraction [205]. It has been shown to induce smooth muscle relaxation and inhibit prostate growth, offering potential treatment for benign prostatic hyperplasia [206].

Studies on honokiol’s effects on prostate cancer cells have revealed that it induces apoptotic DNA fragmentation regardless of androgen responsiveness or p53 status [207]. In mouse models, honokiol inhibits the growth of PC-3 xenografts without causing significant side effects. When combined with docetaxel, honokiol synergistically suppresses cell survival and reduces tumor areas in the C4-2 xenograft model [208].

Honokiol treatment reduces AR protein levels in both androgen-responsive and androgen-independent prostate cancer cells through proteasomal degradation and decreased AR mRNA levels [147]. By targeting AR signaling pathways, honokiol impairs AR-mediated transcriptional activity, enhancing the efficacy of existing prostate cancer therapies and offering potential applications for treating castration-resistant prostate cancer (CRPC).

7.10. Luteolin

The flavonoid luteolin (3′,4′,5,7-tetrahydroxy flavone), known for its anti-inflammatory and antioxidative properties, is naturally found in perilla seeds, celery, green pepper, and parsley. Recent studies have highlighted luteolin’s potential as a therapeutic agent in the management of castration-resistant prostate cancer (CRPC) using a rat model. The anti-CRPC properties of luteolin are primarily attributed to its suppressive effect on AR-V7. In dietary interventions, luteolin has demonstrated efficacy in preventing the onset of early prostate carcinogenesis in TRAP rats without adverse side effects. Additionally, it has been shown to inhibit tumor growth in CRPC by inducing apoptosis. A significant mechanism underlying these effects is the upregulation of miR-8080, which is induced by luteolin supplementation. This miRNA plays a pivotal role in decreasing AR-V7 protein levels, thereby inhibiting tumorigenesis and mitigating resistance to enzalutamide, a commonly used anti-androgen therapy in CRPC [148]. These findings underscore luteolin’s potential to enhance the effectiveness of existing CRPC therapies and its promise as a novel therapeutic strategy targeting AR-V7 and associated pathways, thereby improving treatment outcomes for patients with advanced prostate cancer.

7.11. Quercetin

Quercetin, a flavonoid found in fruits and vegetables, possesses anti-inflammatory, antioxidant, and anticancer properties. It disrupts cancer cell cycles and induces apoptosis. Research has demonstrated quercetin’s therapeutic benefits in various cancers, including prostate cancer. It inhibits androgen receptor (AR) and prostate-specific antigen (PSA) activity, crucial in prostate cancer etiology [209]. Quercetin modulates signaling pathways like PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK1, promoting apoptosis and autophagy, and reducing metastasis by lowering VEGF and MMP release [210]. Quercetin’s combination with chemotherapeutic drugs, such as docetaxel, shows enhanced efficacy in reducing cell viability and metastasis. Studies reveal that quercetin combined with docetaxel results in significant apoptosis and PI3K/Akt pathway inhibition. Co-administration of quercetin with docetaxel has shown promising results in docetaxel-resistant xenograft tumor models, indicating potential for more effective and economical treatments with fewer side effects [211]. Further research is needed to fully understand quercetin’s role in enhancing chemotherapy and reducing drug resistance in prostate cancer [212].

7.12. Resveratrol

Resveratrol, a naturally occurring stilbenoid, demonstrates significant anti-cancer properties with minimal side effects [213]. It effectively targets the tumor microenvironment (TME) and androgen receptor (AR) in prostate cancer [214], inducing growth inhibition, cell cycle arrest, apoptosis, and metastasis suppression [215]. Resveratrol generates reactive oxygen species (ROS) [216], causing oxidative stress and cellular damage, leading to cancer cell apoptosis through multiple signaling pathways [217]. However, its poor solubility, low bioavailability, and rapid metabolism limit its efficacy. Utilizing nanoparticles as a delivery system can enhance resveratrol’s stability, solubility, and therapeutic effectiveness in prostate cancer cells. This enhanced delivery system ensures more effective drug performance, addressing the common limitations faced by traditional administration methods and making resveratrol a promising candidate for advanced prostate cancer treatments.

7.13. Silibinin

Silibinin, a flavolignan extracted from the fruits of Silybum marianum (milk thistle), is increasingly recognized as a promising candidate for cancer prevention and treatment. Silibinin exerts its anti-cancer effects by impeding cell proliferation through targeting the androgen receptor (AR). Notably, silibinin has been shown to decrease the expression of prostate-specific antigen (PSA), an AR target gene, particularly under androgen-stimulated conditions. This reduction in PSA expression highlights silibinin’s potential role in disrupting AR signaling pathways, making it a viable therapeutic agent for managing prostate cancer, including castration-resistant prostate cancer (CRPC) [218].

7.14. Sulforaphane

Sulforaphane (SFN), a natural compound abundantly found in broccoli sprouts and various cruciferous vegetables, demonstrates potent inhibitory effects on the expression of both full-length androgen receptor (AR-FL) and the variant AR-V7 [70,99]. Moreover, research indicates that SFN enhances the anticancer efficacy of anti-androgens by exerting its suppressive action on AR [152,219]. The intricate interplay between AR and other signaling pathways in PCa significantly modulates AR’s transactivation capacity, thereby contributing to early development of CRPC [220]. The dysregulated expression of AR, in conjunction with other signaling pathways supporting and propagating PCa cells, leads to the upregulation of target genes pivotal for cell survival, proliferation, secretion, and lipid synthesis. These genes encompass a wide array of transcription factors, cell cycle regulators, and proteins crucial for cancer progression. Thus, investigating the crosstalk between AR and key signaling pathways in PCa emerges as a crucial strategy to impede the progression of PCa and hinder its transformation into CRPC [221].

7.15. Triptolide

Triptolide (TPL), derived from the Chinese herb Tripterygium wilfordii, is recognized as a potent cancer-preventive substance. It exerts its effects by inhibiting XPB/CDK7-mediated phosphorylation of both full-length androgen receptor (AR-FL) and the variant AR-V7 at Ser515. Notably, TPL demonstrates a significant inhibitory effect on the binding of androgen-induced AR to the androgen response element (ARE) located in the enhancer region of the PSA/KLK3 gene. This mechanism underscores the potential of TPL as a therapeutic agent for targeting AR-driven pathways in prostate cancer [154].

8.1. Cytotoxic Effects of Plant Polyphenol Compounds in Cancer Treatment

Research indicates that flavonoids, a significant group of plant polyphenols, exhibit cytotoxic effects primarily at high micromolar concentrations. Factors influencing plasma levels of dietary flavonoids include functional categories and daily consumption. However, achieving sufficient plasma concentrations through oral dosing to elicit antiproliferative and cytotoxic effects remains challenging [222]. Plant-based antioxidants such as flavonoids, phenolic acids, tannins, and phenolic diterpenes are central to this action. Interestingly, flavonoids like quercetin can convert into cytotoxic prooxidant metabolites in vitro, highlighting their dual role [223]. Therefore, while flavonoids constitute two-thirds of dietary phenolics, their therapeutic efficacy relies on high intake levels, which are difficult to achieve through oral consumption alone [223].

8.2. The Limitations and Challenges of Using Natural Compounds in Treating CRPC

Plant extracts and their various constituents have garnered attention for their therapeutic potential, particularly in reducing cancer-related mortality. Despite their ancient use, it was not initially evident that these natural substances could be effective. Researchers have identified numerous herbal compounds with anticancer properties, but several challenges remain. These include broad-spectrum activity, toxicity, water insolubility, passive targeting, and herb-drug interactions. For instance, clinical trials with pomegranate juice and extract over six months did not significantly reduce plasma PSA levels due to the low serum dose and the time-consuming nature of these studies, which often take months to years to yield results [224].

To achieve successful therapeutic outcomes, several constraints with natural substances must be addressed. A significant limitation of many natural compounds is their limited bioavailability, making it challenging to reach effective in vivo concentrations through oral intake. Long-term toxicity of these phytochemicals needs further investigation due to the high amounts ingested during treatment. Comprehensive molecular target profiling is also necessary to alleviate concerns about the potential adverse effects of their multi-targeting efforts. Clinical trial data on phytochemicals are limited compared to numerous pre-clinical studies, indicating the need for more clinical research at every stage.

Additionally, discovering new phytochemicals with improved bioavailability and anti-cancer potential should be a priority. Despite these obstacles, natural products hold promise as supplementary or alternative cancer treatments. Elucidating precise mechanisms of action based on chemical structure will aid in discovering new natural compounds with notable anti-cancer properties, beneficial for drug development and combination optimization. This can lead to less toxic or non-toxic treatments for prostate cancer, offering substantial health benefits [143]. Most research focuses solely on drug efficacy, often overlooking potential side effects, and some studies have yet to fully clarify the precise molecular mechanisms of active ingredients in herbal remedies for prostate cancer therapies. Therefore, research on medication safety and network pharmacology analysis techniques should be integrated into studies on plant medicine molecules. Detailed experimental verification and extensive drug target protein screening can lead to a better understanding of their mechanisms of action [225].

8.3. Limitation of Castration-Resistant Prostate Cancer Treatment

As prostate cancer progresses to the castration-resistant stage, therapeutic options become increasingly limited compared to early stages [226]. While chemotherapy, newer hormonal treatments, immunotherapy, and targeted medicines can provide temporary disease control, they are not curative. Eventually, resistance to these treatments may develop as well. Prostate cancer cells may become resistant to hormone therapy after initially responding to Androgen Deprivation Therapy (ADT), leading to the emergence of CRPC [227]. The reasons behind this resistance are intricate and not completely comprehended, posing challenges for effective intervention [227]. Castration-resistant prostate cancer is a heterogeneous disease characterized by variations in biology, genetic alterations, and therapy response across patients [228]. The diversity in CRPC patients presents a challenge in developing targeted medicines that are effective for all individuals [229]. Therapies for CRPC, such as chemotherapy, targeted therapy, and immunotherapy, may result in notable adverse effects such as fatigue, nausea, diarrhea, alopecia, immunosuppression, and neuropathy [230]. Balancing these adverse effects with therapy effectiveness is crucial for optimizing patient results.

New treatments for CRPC, such as targeted medicines and immunotherapies, may come with high costs, which may hinder some patients from accessing them, especially in areas with scarce healthcare resources or insufficient insurance coverage. The prognosis for people with CRPC remains unfavorable, particularly when the cancer has metastasized to other organs, despite therapy improvements. Newer treatments show better overall survival and progression-free survival than traditional therapies, although the extent of improvement varies among individuals, and long-term results are still rather limited. Managing CRPC requires carefully weighing the potential therapeutic benefits against its effects on quality of life. Some therapies may extend lifespan but have notable adverse reactions that can impact physical capabilities, emotional health, and overall well-being. Collaborative decision-making between patients and healthcare providers is essential in taking these aspects into account when selecting treatment alternatives. Prostate cancer is a complex disease that poses numerous challenges in its diagnosis and treatment. Despite advancements in medical science, the management of prostate cancer often involves navigating through a range of treatment options, each with its own set of limitations and potential side effects. Surgical interventions such as radical prostatectomy and radiation therapy aim to remove or destroy cancerous cells, but they can lead to complications such as urinary incontinence and erectile dysfunction. Hormone therapy, which suppresses the production of testosterone to slow cancer growth, may result in side effects like hot flashes and loss of libido. Moreover, the emergence of CRPC, where the cancer progresses despite hormonal therapy, further complicates treatment. While newer therapies such as chemotherapy, targeted therapy, and immunotherapy have shown promise in extending survival, they also bring their challenges, including toxicity and resistance development.