VCOM Louisiana Research Day Program

Pharmacology

Ahmad F. Chaban, OMS-III; Dalal Dawud, B. Pharm 1 ; Shams G. Shams 1 , PhD; Emily Schierer 1 , OMS-III; Ahmed Moustafa 3 , PhD; Hassan Y. Ebrahim 2 , PhD; Khalid El Sayed 2 , PhD; Zakaria Y. Abd Elmageed, PhD Department of Biomedical Sciences 1 , Edward Via College of Osteopathic Medicine (VCOM), Monroe, Louisiana; School of Basic Pharmaceutical and Toxicological Sciences 2 , College of Pharmacy, University of Louisiana Monroe, Louisiana; Tulane Center of Ageing 3 , School of Medicine, Tulane University, New Orleans, LA 55 INHIBITION OF NEUTRAL SPHINGOMYELINASE 2 SENSITIZES AGGRESSIVE PHENOTYPES OF PROSTATE CANCER CELLS TO ENZALUTAMIDE TREATMENT

Background: Prostate cancer (PCa) is first diagnosed cancer in men above the age of 65, with an estimated 288,300 cases and 34,700 deaths in 2023. Androgens are the main driving-force for development of PCa. The development of castration-resistant prostate cancer (CRPC) is the current major challenge. The first option for CRPC patients’ treatment is antiandrogens and androgen biosynthesis inhibitors. Unfortunately, up to 25% of patients develop de novo resistance to enzalutamide and the rest of patients who initially responded will develop acquired resistance within few months. Understanding the molecular mechanisms underlying the development of drug-resistance is urgently need. Therefore, this study aims to determine the inhibitory effect of neutral Sphingomyelinase 2 inhibitor, DPTIP, and anti androgen “enzalutamide” in combination on treatment of CRPC cells. Methods: CRPC PC-3 and CWR-R1ca cells were treated with different concentrations of DPTIP and enzalutamide, individually and in combination. The half-maximal inhibitory concentration (IC50) for each drug was determined. The effect of 0.1 and 0.5 IC50 of drug combinations on suppressing PCa aggressiveness was assessed in vitro by cell proliferation, migration, and invasion assays.

Results: The IC50 of DPTIP for PC-3 and CWR-R1ca cells was 39.3 and 10.31 µM and for enzalutamide was 13.29 and 12.64 µM, respectively. Treatment of CRPC cells with 0.1 and 0.5 IC50 of the two drugs showed a significant decrease (p<0.001) in cell proliferation, colony formation and migration. The expression of nSMase2 and NF-kB p65 was inhabited by DPTIP after 48h of the treatment. Conclusions: The study constitutes an invocative effort for treatment of the most aggressive forms of PCa cells through dual targeting of androgen receptor and nSMase2 activity. Interfering with these two pathways inhibited the CRPC cells which can lead to an efficient treatment and improve the overall survival of PCa patients.

71 2023 Via Research Recognition Day