ABC Transporter‐Mediated Multidrug Resistance in Prostate Cancer Cells

Abstract

BackgroundProstate cancer is the second most diagnosed cancer in men. The high incidence of prostate cancer has been attributed to a failure in chemotherapy. Studies show that energized ATP Binding Cassette proteins cause 50% of the failure in chemotherapy. This study focuses on inhibiting ATP Binding Cassette (ABC) protein‐mediated drug resistance in prostate cancer treatment by using Poly Lactic‐co‐Glycolic Acid (PLGA) nanoparticle to deliver SC‐514 and 3‐Bromopyruvate (3‐BPA).Objective of studyThis 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.MethodBioassays used in this preliminary study include trypan blue exclusion, MTT tetrazolium, NBT, cell titer glow, fluorescence microscopy, multidrug resistance efflux.ResultsOne‐way ANOVA comparing the impact of 3‐BPA, SC‐514 and the combination of 3‐BPA and SC‐514 on LNCaP cells at 24hrs of treatment shows that p=0.00023. Time‐dependent treatment of LNCaP cells with 3‐BPA, SC‐514, and a combination of 3‐BPA and SC‐514 after regression analysis shows the following p values: 24hrs (0.00023), 48hrs (0.00003), 72hrs (0.000000152), 96hrs (0.000000049). ROS level of LNCaP cells treated with 3‐BPA (r=−0.5, p=0.11), SC‐514 (, r=− 0.72 p=0.04,) and 3‐BPA + SC‐514 (r=−0.58, p=0.04) shows no significant difference in ROS modulation (p=0.54). There was a weak to moderate correlation between ROS released and cell death. There was a weak correlation between percentage ROS induced and percentage apoptotic death. There was a positive correlation between the concentration of the drug and cell death. 3‐BPA and/or SC‐514 depleted intracellular ATP in DU‐145 cells. There was a time‐dependent effect of 3‐BPA and/or SC‐514 on cell death. SC‐514 and/or 3‐BPA are substrates for MDR1. 3‐BPA and/or SC‐514 potentially block MDR1. DU‐145 prostate cancer cells efflux dyes within 15 minutes.Conclusion3‐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 prostate cancer cells exists via a mechanism other than reactive oxygen species (ROS) induction.Support or Funding InformationFellowships and grantsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.