Nanoencapsulation of Curcumin-Piperine Complex for Targeting CYP17A1 in Castration-Resistant Prostate Cancer

Abstract ID 127676 Poster Board 238 Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). During the past decade, new treatments have targeted the androgen signaling axis either by inhibiting the binding of androgens to androgen receptor (AR) and AR nuclear translocation or by inhibiting androgen production through the cytochrome P450 enzyme CYP17A1. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. Current treatments targeting CYP17A1 in prostate cancer are not very specific. In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate is a recognized challenge. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. CYP17A1 and CYP21A2 assays were carried out using radiolabelled substrates. We performed full steroid profiling with LC-MS/MS, as well as gene and protein expression studies by qPCR and western blots. Prostate cancer cell proliferation assays were carried out using LNCaP, VCaP, PC3, and DU145 carcinoma cell lines. Cell cycle analysis was done using flow cytometry. Experiments performed in adrenal NCI-H295R cells showed that our curcumin-piperine nanoparticles efficiently suppress the CYP17A1-17 α-hydroxylase activity that converts progesterone to 17-hydroxy-progesterone. Our nanoparticles also demonstrated inhibitory effects on the CYP17A1-17,20 lyase activity, which converts 17 α-hydroxy-pregnenolone to dehydroepiandrosterone (DHEA). Compared to the effect of known CYP17A1 inhibitor abiraterone in NCI-H295R cells, our nanoparticles did not_show any inhibitory effects on CYP21A2-hydroxylase activity, which metabolizes the production of deoxy corticosterone and 11-deoxycortisol. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, gene and protein expression analysis by qPCR and western blot investigations of the interaction of nanoparticle preparations on cells did not show any changes, and flow cytometry analysis did not reveal cell cycle effects. We further confirmed the efficacy of our nanoformulation by testing its impact on the growth of androgen-sensitive (LNCaP, VCaP) and insensitive (PC3, DU145) prostate cancer cell lines. Notably, steroid profiling by LC-MS/MS revealed that nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while not affecting CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as an option for targeting CYP17A1, either alone or in combination with other drugs loaded on nanoparticles, for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. This study was funded by Cancer Research Switzerland grant number: KFS 5557-02-2022 to Amit V Pandey and a Swiss Government Excellence Scholarship grant number 2022.0470 to Jibira Yakubu.