VCOM Louisiana Research Day Program Book 2024

Biomedical Research: Section 2

Dalal Dawud 1 , PhD Candidate, Kalid El Sayed 2 , PhD and Zakaria Y. Abd Elmageed 1 , PhD 1 Department of Biomedical Science, VCOM; 2 School of Basic Pharmaceutical & Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe 16 INVESTIGATING THE THERAPEUTIC EFFICACY OF COMBINED TREATMENT OF CHLORPROMAZINE AND ENZALUTAMIDE ON CASTRATION-RESISTANT PROSTATE CANCER CELLS: A COMPREHENSIVE IN VITRO AND IN VIVO STUDY

Background: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, prompting the exploration of novel therapeutic combinations. Drug combinations is one of the most effective strategies to reduce metastasis in patients with mCRPC. Objective: In this study, we investigated the individual and combined effects of chlorpromazine, an antipsychotic agent, and enzalutamide, an androgen receptor antagonist, on four CRPC cell lines; CWR-R1ca, CWR 22RV1, PC-3, and PC-3M. Methods: Cell toxicity, colony formation and scratch assays in addition to Western blot analysis were performed to comprehensively evaluate the therapeutic effect of individual and combined chlorpromazine and enzalutamide. The half-maximal inhibitory concentration (IC50) for each treatment was determined using the MTT assay. The effect of individual and combined drugs was evaluated in preclinical prostate cancer mouse model using CWR-R1ca cells. Results: Individual treatments demonstrated noteworthy inhibitory effects on cell viability, while the combined regimen exhibited a

synergistic reduction in cell viability in all mCRPC cells. Scratch assays revealed a significant attenuation of cell migration, indicating a potential impairment of metastatic capabilities. Colony formation assays further supported the combination’s robust anti proliferative impact. To extend our findings using in vivo study, Foxn1nu/nu (nude) mice were xenografted with luciferase-tagged CWR-R1ca cells treated with chlorpromazine, enzalutamide, or their combinations. In vivo imaging using the Perkin and Elmer IVIS imaging system allowed real-time monitoring of tumor growth. Baseline and endpoint imaging demonstrated a significant reduction in tumor bioluminescence in the combined treatment group, outperforming individual treatments. On the molecular level, Heme oxygenase 1 (HMOX-1) protein was overexpressed in the combined treatment as compared to the individual drugs. Conclusions: Our comprehensive approach provides an unequivocal understanding of the therapeutic potential of combining chlorpromazine with enzalutamide. The robust drug combination was associated with significant overexpression of HMOX-1 protein. The observed synergistic effects underscore the promise of this dual treatment strategy for addressing mCRPC, offering a multifaceted

approach to impede both cell proliferation and metastasis.

29 2024 Via Research Recognition Day