Abstract 127: Pre-exposure to stress-inducing agents increase the anticancer efficacy of focused ultrasound against aggressive prostate cancer cells

Abstract

Abstract Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e. LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically-tested drugs that increase Ox-stress (i.e. CDDO-me) or ER-stress (i.e. Nelfinavir). As compared to standalone FUS, significant (p<0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability, and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels in surviving cells. Thus, a combined MCD therapy may be an effective noninvasive approach towards targeted elimination of aggressive PCa cells. Citation Format: Hakm Y. Murad, Partha K. Chandra, Charles A. Kelly, Namrata Khurana, Heng Yu, Emma P. Bortz, Shirley N. Hong, Debasis Mondal, Damir B. Khismatullin. Pre-exposure to stress-inducing agents increase the anticancer efficacy of focused ultrasound against aggressive prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 127.