Dataset Information

Natural Product-Based Studies for the Management of Castration-Resistant Prostate Cancer: Computational to Clinical Studies

ABSTRACT: Background: With prostate cancer being the fifth-greatest cause of cancer mortality in 2020, there is a dire need to expand the available treatment options. Castration-resistant prostate cancer (CRPC) progresses despite androgen depletion therapy. The mechanisms of resistance are yet to be fully discovered. However, it is hypothesized that androgens depletion enables androgen-independent cells to proliferate and recolonize the tumor. Objectives: Natural bioactive compounds from edible plants and herbal remedies might potentially address this need. This review compiles the available cheminformatics-based studies and the translational studies regarding the use of natural products to manage CRPC. Methods: PubMed and Google Scholar searches for preclinical studies were performed, while ClinicalTrials.gov and PubMed were searched for clinical updates. Studies that were not in English and not available as full text were excluded. The period of literature covered was from 1985 to the present. Results and Conclusion: Our analysis suggested that natural compounds exert beneficial effects due to their broad-spectrum molecular disease-associated targets. In vitro and in vivo studies revealed several bioactive compounds, including rutaecarpine, berberine, curcumin, other flavonoids, pentacyclic triterpenoids, and steroid-based phytochemicals. Molecular modeling tools, including machine and deep learning, have made the analysis more comprehensive. Preclinical and clinical studies on resveratrol, soy isoflavone, lycopene, quercetin, and gossypol have further validated the translational potential of the natural products in the management of prostate cancer.

SUBMITTER: Singla R

PROVIDER: S-EPMC8560712 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Enzalutamide is useful for the treatment of castration-resistant prostate cancer (CRPC). Despite its usefulness, adverse events (AEs) sometimes force patients to discontinue treatment. To maximize patient care, we developed an ambulatory care pharmacy practice that allows collaboration between a pharmacist and urologist to manage patients with CRPC receiving enzalutamide. In this study, we investigated the efficacy of this collaborative management. Methods: A retrospective chart review of 103 patients with CRPC receiving enzalutamide in our hospital between May 2014 and December 2020 was performed. Our collaborative management was implemented in October 2016. Before being examined by urologists, patients visited the oncology pharmacy consultation room for a face-to-face consultation, wherein the oncology pharmacists assessed factors such as adherence to enzalutamide, any AEs and their grades, and provided their suggestions to the urologists. The time to enzalutamide discontinuation and prostate-specific antigen progression were compared between patients who started enzalutamide before (n = 41) and after (n = 62) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with enzalutamide discontinuation. Results: After implementing collaborative management, the pharmacists had 881 patient consultations. Among the 476 suggestions from pharmacists, 345 were accepted by urologists. The most frequent suggestion was supportive care in enzalutamide treatment (224 suggestions). Multivariate analysis showed that collaborative management [hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31-0.89, p = 0.017] and higher prostate-specific antigen (PSA; HR 2.41, 95% CI 1.36-4.28, p = 0.003) were significantly associated with enzalutamide discontinuation. The median time to discontinuation (18.9 vs. 7.6 months, p = 0.012), time to discontinuation due to AEs (not reached in both groups, p = 0.001), and time to PSA progression (13.3 vs. 5.8 months, p = 0.002) were all significantly longer in the after group. Conclusions: We implemented a pharmacist-urologist collaborative management program for outpatients with CRPC receiving enzalutamide. The results revealed that collaborative management was useful for prolonging the time to enzalutamide discontinuation.

Project description:BackgroundCastration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC.MethodsIn this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts.ResultsMyricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone.ConclusionsThese results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.

Dataset Information

Natural Product-Based Studies for the Management of Castration-Resistant Prostate Cancer: Computational to Clinical Studies

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets