This section summarizes and discusses the past studies that include the use of CBZ in combination with other chemotherapy agents such as docetaxel, carboplatin, genistein, radiotherapy, antiandrogen therapy, mitoxantrone, and tasquinimod.

The previous investigations have demonstrated that the combination of dual androgen receptor-targeting medications (abiraterone + enzalutamide) with a combination of taxanes (docetaxel + CBZ) did not increase the survival rates of patients with prostate cancer. This was caused by the fact that all of these medications block the androgen receptor signaling by inhibiting the same transport mechanism, androgen receptor nuclear transport. Moreover, it was shown that the activity of docetaxel after abiraterone treatment was less than anticipated, with a median overall survival of just 12.5 months, as opposed to 19 months in the TAX327 trial (which treated patients with a combination of taxanes only). In comparison to participants in the TAX327 (48%) and a similar cohort of abiraterone-naive patients (54%), PSA responses were found to be lower (26%) (Mezynski et al. 2012; van Soest et al. 2013).

The median progression-free survival for patients with HRPC who took the CBZ and carboplatin (n = 81), an anti-neoplastic drug that suppresses DNA repair and synthesis in cancer cells, in combination (a CBZ dose of 25 mg/m² and carboplatin of AUC 4 mg/mL per min) was enhanced from 4.5 months to 7.3 months after 31 months of following up compared with patients treated with CBZ alone ((n = 79) and a CBZ dose of 25 mg/m²). However, the grade 3–5 adverse effects, such as fatigue, anemia, neutropenia, and thrombocytopenia, were more noticeable in the combination group compared with CBZ alone, but no treatment-related deaths had occurred in both groups. Moreover, the percentages for these treatment-related adverse events were found as follows: fatigue (7 [9%] of 79 in the CBZ group vs. 16 [20%] of 81 in the combination group), anemia (3 [4%] vs. 19 [23%]), neutropenia (3 [4%] vs. 13 [16%]), and thrombocytopenia (1 [1%] vs. 11 [14%]) (Corn et al. 2019).

The IC₅₀ of CBZ against PC3-Luc prostate cancer cells was also improved when it was used with genistein, an isoflavone compound and angiogenesis inhibitor derived from a plant called Genista tinctoria, by 2-fold with a combination index of 0.693 (where a combination index < 1 refers to synergism and > 1 confirms the antagonism) at a concentration of 5 µg/mL for genistein and 20 nM for CBZ. The in vivo results using the xenograft model of PC3-Luc cells also showed that the average tumor sizes were found to be 2008.7 ± 214.1 mm³ (control), 1913.5 ± 248.2 mm³ (genistein), 1650.8 ± 731.4 mm³ (CBZ), and 419.8 ± 249.2 mm³ (combination) (Zhang et al. 2013).

Lin et al. (2020) have also reported that the 5-year biochemical disease-free survival for 20 HRPC patients (who received triple therapies: CBZ 4 mg/m² weekly + radiotherapy with a total dose to the prostate of 75.6 gray + second-generation antiandrogen therapy (gonadotropin-releasing hormone), namely, Enzard^® (enzalutamide) for a total of 24 to 28 months with a median follow-up time of 56 months) was 73%. In contrast, four of the patients were unable to finish chemotherapy because of dose-limiting toxicities (e.g., rectal bleeding, diarrhea, and raised transaminase), and 75% of these patients had very high-risk prostate cancer (three patients increased their PSA levels and 13 patients had undetected PSA levels).

Mitoxantrone, a type II topoisomerase inhibitor, was also used to synergize the anticancer activity of CBZ against prostate cancer. Furthermore, CBZ 25 mg/m² + Mitoxantrone 10 mg/m² were administered on day 1 of a 21-day cycle by 23 patients with HRPC. The PSA levels were declined by 50% among 12 patients. The median duration of response was found to range between 4.9 and 10.0 months. However, the majority of these patients developed adverse events related to this combination as follows: n = 6 (sepsis and febrile neutropenia), n = 9 neutropenia, and n = 3 thrombocytopenia (Aggarwal et al. 2017).

Consistent with the above studies, PSA levels were also dropped by more than 30% in 16 out of 25 patients with HRPC who received oral tasquinimod, an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer, at one of three escalating dose levels (0.25 mg, 0.5 mg, and 1.0 mg once daily) with 25 mg/m² CBZ. For these patients, the median composite progression-free survival was 8.5 months. The combination-related toxicities among 15 patients include grade 3 fatigue, sensory neuropathy, atrial fibrillation, liver function, and grade 4 febrile neutropenia abnormalities (Armstrong et al. 2017). To summarize, the combination of CBZ with different chemotherapies resulted in a higher CBZ activity, but it also raised treatment-related toxicities. In patients with advanced prostate cancer, nanocarriers were crucial to deliver CBZ selectively to prostate cancer and decrease adverse events.

The antiproliferative activities of ketoconazole, diethylstilbestrol, corticosteroids, digoxin, itraconazole, megestrol, disulfiram, mifepristone, statin, and metformin against prostate cancer were previously evaluated in the literature (Table 1).

Ketoconazole, an antifungal drug, should be avoided by those who have HRPC, since it has been demonstrated to be a less potent androgen synthesis inhibitor and has been associated with side effects such as weakness, edema, and diarrhea (Millikan et al. 2003, 2008; Small et al. 2004; Nakabayashi et al. 2006; Ryan et al. 2007; Taplin et al. 2009; Amato et al. 2013; Gil-Bazo et al. 2013; Mostaghel et al. 2014; Lo et al. 2015).

Diethylstilbestrol, an estrogen hormone, has been indicated as an alternative option for orchiectomy in patients with hormone-dependent prostate cancer. Because it works through several mechanisms, including competitive inhibition of the androgen receptor and direct anticancer efficacy in prostate cells, it can also be utilized to treat individuals with HRPC. However, it can result in lethal cardiac events (Manikandan et al. 2005; Shamash et al. 2011).

Corticosteroids such as dexamethasone are given as part of a supportive care therapy plan for patients with advanced prostate cancer who have pain, weakness, and anorexia. Furthermore, they have weak anticancer effects in prostate cancer by decreasing the synthesis of testosterone (Venkitaraman et al. 2015).

Digoxin, a widespread antiarrhythmic drug, has recently suppressed the growth of prostate cancer by 25% through triggering many apoptotic processes, including enhanced interleukin 8, hypoxia-inducible factor 1 inhibition, intracellular calcium influx, and Src kinase activation (Platz et al. 2011; Lin et al. 2014, 2020; Kaapu et al. 2015, 2016). Although digoxin has been linked to a decreased incidence of prostate cancer, retrospective cohort studies have found that digoxin did not correlate to prostate cancer mortality (HR 1.17; 95% CI 0.88–1.57) (Flahavan et al. 2014). Furthermore, there were ten clinical studies conducted on 108,444 participants (15,835 of them were digoxin users). Six studies found a substantial decrease in prostate cancer risk associated with digoxin use (adjusted RR = 0.892, 95% CI: 0.799–0.997, p = 0.044) compared to nonusers. While four of them have revealed a significant correlation between digoxin and greater prostate cancer-specific mortality compared to controls (adjusted HR = 1.142, 95% CI: 1.005–1.297). There was no statistical heterogeneity observed in this study (all I² < 50%, p > 0.1) (Zhao et al. 2021). In conclusion, digoxin had a preventive action on the risk of prostate cancer in men. However, digoxin use was linked to a higher risk of prostate cancer-related mortality. More well-designed studies are needed to adequately interpret the causation of these findings.

Clinical trial studies have demonstrated that itraconazole, megestrol, disulfiram, and mifepristone can be effective in treating prostate cancer. These medications exert their anticancer efficacy through several mechanisms, including blocking the androgen receptor, decreasing the release of reactive oxygen species, and inhibiting the formation of new blood vessels (Dawson et al. 2000; Hayes et al. 2006; Antonarakis et al. 2013; Schweizer et al. 2013).

In 2006, the first epidemiological investigation indicated that statin users had a 61% lower incidence of deadly prostate cancer (RR 0.39; 95% CI 0.19–0.77) than nonusers. The largest study to date had around 11,772 men with nonmetastatic prostate cancer with 1791 deaths during follow-up. After controlling for potential confounders, post-diagnostic clinical follow-up had shown that statin was associated with a 24% decreased risk of cancer-specific death (hazard ratio, HR 0.76; 95% CI 0.66–0.88) (Stopsack et al. 2016; Cao et al. 2023; Papagiannakis et al. 2025). A recent study found that males who took statins had a longer time to progress on ADT compared to nonusers (Dos Santos et al. 2024).

According to in vitro studies, metformin can suppress prostate and other cancers through several mechanisms, involving effects on both cancerous and non-cancerous cells. Two high-quality population-based studies evaluated the relationships between metformin use and death following a diagnosis of prostate cancer. In Ontario, Canada, Margel et al. (2013) first examined 3837 diabetic males who were over 66 years old and had prostate cancer. A 24% decreased risk of prostate cancer-specific death was linked to every extra six months of metformin use (95% CI 11–36%). Lower all-cause mortality was also substantially linked to metformin. Bensimon et al. (2014) found no evidence of overall prostate cancer-specific mortality (RR 1.09; 95% CI 0.51–2.33) in their trial, which involved 935 males from the United Kingdom. A recent meta-analysis of all studies that took diabetes diagnosis into account found that metformin was linked to better overall survival and lower biochemical recurrence among patients with prostate cancer (Joshua et al. 2022; de Oliveira et al. 2025). However, the results for mortality specific to prostate cancer were inconsistent, but the study of Margel et al. (2013) was the most dominant.

As usual, plants provide an abundant supply of the taxane chemotherapeutics, including CBZ. This section explores the wide spectrum of natural compounds, such as isoflavones, naphthoquinones, and polyphenols, for which anticancer action against prostate cancer has been identified. Furthermore, these agents can exert their anticancer activity via various mechanisms such as inhibition of angiogenesis, reducing the growth and metastasis of prostate cancer cells, targeting tumor suppressor genes, decreasing the production of androgenic hormones, and using photodynamic properties of some plant families.

Previous investigations have shown that the protocatechuic acid from Punica granatum, polysaccharides from mushrooms Ganoderma lucidum, Trametes versicolor, Grifola frondosa, and Rubus occidentalis, as well as resveratrol from Vitis vinifera, mainly induced apoptosis and impaired the metastasis of prostate cancer cells by inhibition of the angiogenesis of prostate tumor cells (Panda et al. 2022). Besides, the additional mechanisms for Punica granatum (pomegranate) were also involved in reducing oxidative stress biomarkers in tissue, stimulation of apoptosis executor caspase 3, accumulation of reactive oxygen species, and inhibition of matrix metalloproteinases (MMP2/MMP9) that control the migration and invasion of cancer cells (Deng et al. 2017; Johari et al. 2022). The IC₅₀ of docetaxel and flutamide (nonsteroidal antiandrogen used primarily to treat prostate cancer) against PC3-Luc and LNCaP prostate cancer cells was reduced by 50% following a combination with Ganoderma lucidum (Rahimnia et al. 2023). The latest study has shown that Ganoderma lucidum can also target signal transducer and activator of transcription 3 (STAT3), which is involved in the proliferation and metastasis of prostate tumor cells (Zhou et al. 2024). The immune system (mainly T-cells and splenic natural killer cells) could also be targeted using Trametes versicolor and Grifola frondosa mushrooms as adjuvants with docetaxel (Habtemariam 2020; He et al. 2022; Li et al. 2024; Lamkhade et al. 2025). Perez (2020) and Fuloria et al. (2022) revealed that Vitis vinifera had not only inhibited angiogenesis but also arrested the G1 phase cell cycle and promoted the activity of apoptosis-associated enzymes. Prostate cancer cell growth was not inhibited by Rubus occidentalis (black raspberry extract), cyanidin-3-rutinoside, or protocatechuic acid during the in vitro study (Eskra et al. 2019).

In this study, it has also investigated whether isoflavones such as genistein and daidzein as well as methoxylated ones (formononetin, biochanin A, and glycitein), which are less polar than compounds containing hydroxyl groups, may be used in conjunction with CBZ to treat hormone-dependent prostate cancer. The anticancer efficacy of genistein is linked to its ability to block angiogenesis. In the meantime, other isoflavones (such as daidzein) have been shown in publications to have antiangiogenic properties. Genistein and daidzein have been suggested to affect the expression of genes that guarantee angiogenesis and metastasis, such as matrix metalloproteinases (ΜΜP-2, ΜΜP-9, ММ-11, МΜ-13, ΜΜ-14), EGF, ANGPT2, and CTGF (Rabiau et al. 2010). Interestingly, Batra et al. (2020) have also found that the testosterone levels of LNCaP and PC-346C CaP prostate cell lines were reduced by approximately 3-fold. Similarly, it has been found that genistein can also interfere with the therapeutic effects of the estrogen receptor antagonist anticancer agent tamoxifen in athymic nude mice (Du et al. 2012). Besides, formononetin was also one of the isoflavones that suppressed proliferation, migration, and invasion of prostate cancer cells. This anticancer effect may occur by inducing expression of a tumor suppressor gene known as early growth response protein 1 (EGR1) and raising the levels of the cell adhesion molecule E-cadherin protein (Liang et al. 2022). In accordance, the percentages of cell viability for PC3-Luc cells were reduced in a time-dose-dependent way after these cells were treated (after 48 hours) with 40 µM of formononetin from 80% to 30% (Wang et al. 2020). Biochanin-A has also demonstrated inhibitory action in prostate cancer by (1) blocking tyrosine kinase events in the signal transduction pathway and (2) disrupting the metabolism of testosterone via stimulating the activity of the enzyme uridine 5-diphospho-glucuronosyltransferase (UDPGT) (Anuranjana et al. 2023; Park et al. 2024). Unfortunately, no research has yet clarified the primary anticancer mechanism of glycitein against prostate cancer.

Undoubtedly, naphthoquinones (like plumbagin, juglone, and droserone) along with anthraquinones such as the hypericin family have anticancer properties. Furthermore, the cellular uptake of plumbagin, a naphthoquinone with anticancer properties obtained from the plant leadwort, loaded within transferrin-bearing liposomes by B16-F10 mouse melanoma, A431 human epidermoid carcinoma, and T98G human brain tumor cells was improved by at least 1.4-fold compared with control liposomes and 2-fold compared with the drug solution. In addition, the intravenous injection of transferrin-bearing liposomes containing plumbagin led to 10% tumor suppression and an additional 10% tumor regression when compared to untargeted liposomes or untreated groups, respectively (Sakpakdeejaroen et al. 2019). In accordance with plumbagin, the survival rates for PC3-Luc and DU145 cells were reduced (after 72 hours) following treatment with 500 μg/mL of juglone up to 46% and 53%, respectively (Mahdavi et al. 2019). No prior study evaluated the potential anticancer activity of droserone against prostate cancer. Among anthraquinones, hypericin and other dianthrones obviously attract attention, especially when used in chemotherapy simultaneously with radiation based on the photodynamic characteristics of hypericins (hypericin, pseudohypericin, protohypericin). For example, the IC₅₀ of the hexane flower extract of Hypericum perforatum L. against PC3-Luc and LNCaP prostate cancer cells was reduced after 72 hours of treatment from 47.04 ± 4.63 µg/mL to 11.06 ± 0.87 µg/mL (for PC3-Luc cells) and from 58.24 ± 0.03 µg/mL to 11.70 ± 0.80 µg/mL (for DU145 cells) (Petrović et al. 2022).

The encapsulation of epigallocatechin-3-gallate, a green tea polyphenol with anti-tumor effects, within transferrin-conjugated vesicles also led to a marked increase in the cellular uptake of this drug (by at least 1.5-fold) in all three cell lines (A431 cells, B16-F10 melanoma cells, T98G fibroblast cancer cells) compared to that reported in control vesicles and the drug solution. Besides, the in vitro anti-proliferative efficacy on cells treated with epigallocatechin-3-gallate loaded in transferrin-bearing vesicles was significantly enhanced when compared to control vesicles, by 1.9-fold for A431 cells, 2.7-fold for B16-F10 cells, and 4-fold for T98G cancer cells (with IC₅₀ ranging from 0.36 ± 0.05 to 1.41 ± 0.17 g/mL for the transferrin-bearing vesicles). Tumor suppression was also observed in 40% of A431 and B16-F10 cancer cells upon intravenous administration of transferrin-bearing vesicles containing epigallocatechin-3-gallate. In addition, animal survival was increased by more than 20 days in comparison to controls (Lemarié et al. 2013).

Computational methods have also been used to investigate potential drug repositioning options for the treatment of HRPC. Kim et al. (2019) used Gene Expression Omnibus, a database repository of high-throughput gene expression data, to acquire gene expression data from cancerous and normal prostate tissue samples from HRPC patients. Moreover, a meta-signature analysis using the metaDE R-project^® program, statistical computing software, was used to identify the expressed genes in HRPC. This software simulates and generates the outcomes based on existing data and research methodologies. For instance, it was shown that the treatment options sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were successful in decreasing the expression of genes related to HRPC, such as MYL9, E2F2, APOE, and ZFP36, with an IC₅₀ of less than 10 µM for all of drugs. Vascular endothelial growth factor (VEGF) plasma levels were found to be significantly greater in HRPC patients than in localized disease patients (Kim et al. 2019). VEGF is also attributed to the progression of other types of cancer. Pazopanib is a multi-targeted VEGF tyrosine kinase inhibitor. It was discovered that pazopanib and lenalidomide have synergistic cytotoxicity in multiple myeloma (Podar et al. 2006). Kim et al. (2019) found that a combination of lenalidomide and pazopanib had the highest synergistic effect with a combination index value less than 0.6 (where a combination index less than 1 indicates the synergism) (Table 2).