Background: Prostate cancer (PCa) is the second most diagnosed cancer in men. The high incidence of prostate cancer has been attributed to failures in conventional chemotherapy. Studies suggest that energized ATP Binding Cassette proteins cause 50% of the failure in chemotherapy. This study focuses on the inhibition of ATP Binding Cassette (ABC) protein mediated drug resistance in prostate cancer treatment. Specifically, Poly Lactic-co-Glycolic Acid (PLGA) nanoparticle will be utilized as a carrier to deliver SC-514 and 3-Bromopyruvate (3- BPA) in various PCa cell lines.
Objective of study: This study aims to: (i) investigate the potential interaction between 3-BPA and SC-514, (ii) reduce treatment-induced ABC mediated multidrug resistance (MDR), and (iii) investigate the signaling pathways involved in ABC transporter mediated MDR. Method: The bioassays used in this study include: trypan blue exclusion, MTT tetrazolium, NBT, LDH cytotoxicity, cell titer glow, multidrug resistance efflux, poly caspase assay, and NF- kB p65 (Total/Phospho) Multispecies InstantOne™ ELISA. One-way ANOVA was utilized to compare the cytotoxic effects of 3-BPA, SC-514 and the combination of 3-BPA and SC-514 on prostate cancer cells (DU-145 cells and PC-3 cells).
Results: There was a positive correlation between the concentration of drug and cell death. There was a weak correlation (r = 0.19) between percentage ROS induced and percentage apoptotic death. Results based on cell titer glow assay suggested that 3-BPA and/or SC-514 depleted intracellular ATP in DU-145 cells and PC-3 cells. SC-514 and/or 3-BPA are substrates for MDR1. 3-BPA and/or SC-514 potentially block MDR1.
Conclusion: 3-BPA and SC-514 has the potential to inhibit multidrug resistance by reducing the intracellular ATP available to ATP Binding Cassette proteins. Apoptotic induction in DU-145 and PC-3 cells appears to occur via a mechanism other than reactive oxygen species (ROS) induction.
Keywords: Resistance; Cell lines; 3-Bromopyruvate; SC-514