The Impact of PLGA Nanoparticle Delivered 3‐Bromopyruvate and SC‐514 on ABC Transporter Mediated Multidrug Resistance in Prostate Cancer Treatment

Abstract

BackgroundAccording to the World Health Organization, prostate cancer is the second most diagnosed type of cancer in men. Stage IV prostate cancer spreads to the lymph nodes and the bones, often leading to a non‐curable bone metastasis in 65–75% of prostate cancer cases. Current research focuses on preventing ABC mediated multidrug resistance (MDR) in prostate cancer treatment by using nano‐carriers to deliver chemotherapeutic agents. Even though prostate cancer heterogeneity has limited the efficacy of therapies reversing ABC transporter‐mediated MDR. 3‐Bromopyruvate (3‐BPA) and SC‐514 separately deplete ATP source of prostate cancer cells regardless of prostate cancer heterogeneity problem.ObjectiveThis goal of this study is to overcome ABC transporter‐mediated MDR during treatment of prostate cancer. This will be achieved by depleting the ATP energy source of ABC transporter proteins with the double action of 3‐BPA and SC‐514. Further draining of ATP energy will be achieved by controlled and prolonged release of 3‐BPA and/or SC‐514 with Poly Lactic Co‐Glycolic (PLGA) acid nanoparticle.MethodTrypan blue assay was used to determine the percentage cell viability of LNCaP cells (79.5%) and the number of cells per ml (84,000 cells per ml). 5000 cells were seeded in each well of the 96‐well microtiter plate. NBT assay was used to estimate Reactive Oxygen species(ROS) modulation of LNCaP cells after treatment. LDH assay was used to assess the cytotoxicity of treatment group. MTT assay was used to assess cell viability of LNCaP cells.ResultsOne‐way ANOVA analysis of percentage cell viability in LNCaP cells treated for 24 hrs with 3‐BPA (R2= 0.51, p=0.01), SC‐514 (R2= 0.83, p=0.001 IC‐50=70 μM) and 3‐BPA + SC‐514 (R2= 0.87, p=0.001, IC‐50=68 μM) indicated a probability level of 0.03. Treatment for 48 hrs with 3‐BPA (R2=0.84, r=−0.91, p=0.00061), SC‐514 (R2= 0.47, r=−0.7, p=0.07), and 3‐BPA + SC‐514 (R2=0.59, r= −0.95, p=0.00024) indicated a probability level of 0. 00003. Time dependent treatment (24 hrs, 48 hrs, 72 hrs and 96 hrs) shows that cell viability of treated LNCaP cells decrease with time. When 24 hrs was compared with 48 hrs, p=0.00000015 and when 72 hrs was compared with 96 hrs, p=0.000000049. Probability levels between treatment groups (3‐BPA, SC‐514 and 3‐BPA + SC‐514) decreases with time: 24 hrs (p= 0.00023) > 48 hrs (p= 0.00003) > 72 hrs (p=0.000000152) > 96 hrs(p=0.000000049). One‐way ANOVA analysis comparing percentage ROS level of LNCaP cells treated with 3‐BPA (R2 = 0.30, r=−0.5, p=0.11), SC‐ 514 (R2 =0.47, p=0.04, r=− 0.72) and 3‐BPA + SC‐514(R2 = 0.36, r=−0.58, p=0.04) indicated a probability level of p=0.54.ConclusionIn conclusion, 3‐BPA and SC‐514 separately inhibit proliferation of prostate cancer cells. There might be other mechanism influencing the interaction between 3‐BPA and SC‐514 other than ROS modulation. Combination treatment had a lower IC‐50 compared to mono‐treatment of the drug. Further findings from this study will give insight on how inhibition of survival pathways, can impact carcinogenesis and ABC transporter‐mediated MDR in prostate cancer treatment.Support or Funding InformationFlorida Atlantic University Fellowships and ScholarshipsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.