Abstract 70: Oxidative stress and cell death in multidrug-resistant cancer

Abstract

Abstract Reactive oxygen species (ROS) are constantly generated in mitochondria as a consequence of normal cellular metabolic reactions and play vital roles in cell signaling and homeostasis. Prolong production of elevated levels of ROS may lead to oxidative damage, genetic instability, and genetic mutation causing cancer initiation and progression. One proposed therapeutic strategy is to alter oxidative stress from a ROS-induced tumor promoting event to a ROS-induced apoptotic signaling to kill cancer cells. Most ROS inducing therapeutic agents initially induce ROS to kill cancer cells by apoptosis; however, prolonged exposure of such drugs may increase ROS scavenging enzymes resulting in a reduced ROS levels and an adaptive microenvironment that makes cancer cells resistant to the same ROS-inducing therapeutic agents. Chronic exposure of ROS may also upregulate the multidrug resistance associated protein expression in cancer cells. We hypothesize that induction of oxidative stress may sensitize drug resistant cancer cells leading to cell death. We used two pairs of cell lines, a mitoxantrone sensitive and mitoxantrone resistant MCF7 human breast adenocarcinoma (MCF7/MCF7MX) and a H460 non-small lung cancer cell line (H460/H460MX) for our experiments to study the impact of oxidative stress on drug resistance. We employed western blot, ELISA assays, and FACS analysis to determine the total and specific protein oxidative carbonylation, protein aggregation, and cell death by apoptosis or necrosis. At basal level, both mitoxantrone resistant MCF7MX and H460MX cells showed slightly lower level of total protein carbonylation compared to their mitoxantrone sensitive counterparts. Chemical induction of oxidative stress by external sources increased the total protein carbonylation and cell death in both mitoxantrone sensitive and resistance cancer cells. We also observed an increase in protein aggregation with increasing oxidative stress. Our results indicate that oxidative stress-induced protein oxidation by carbonylation and aggregation of oxidized protein which may sensitize drug resistant cancer cells leading to cell death. Citation Format: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao. Oxidative stress and cell death in multidrug-resistant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 70.