Abstract 2645: PEITC induces cell death in melanoma cells through redox mechanisms

Abstract

Abstract Melanoma is one of the deadliest types of cancers accounting for about 80% of skin cancer deaths. Reactive oxygen species (ROS), produced by the mitochondrial respiratory chain and other biochemical mechanisms, play a critical role in melanoma progression through activation of transcription factors AP-1 and NF- κB and loss of E-cadherin. However, a further elevated level of ROS in cells, beyond a certain cellular threshold, may lead to mitochondrial damage, cytotoxicity and subsequent cell death. Hence, increasing ROS levels by either activating a ROS-generating enzyme or by depletion of antioxidants is a plausible strategy to induce cell killing in melanoma cells. The natural compound β-phenylethyl isothiocyanate (PEITC) found in cruciferous vegetables exhibits significant antitumor activity. Recent studies demonstrated that PEITC selectively induced cancer cell death by disabling the glutathione antioxidant system. Based on these observations, we hypothesize that PEITC may preferentially eliminate melanoma cells through ROS-mediated mechanism due to the increased basal ROS levels in melanoma cells and their high dependence on glutathione. To test this hypothesis, the cytotoxic effect of PEITC was tested in a panel of melanoma cell lines in comparison with normal melanocytes. Our results demonstrated that PEITC had time- and concentration-dependent antiproliferative effect in melanoma cells. The inhibitory effect is melanoma specific, since PEITC had minimum cytotoxic activity in normal melanocytes. Further analysis of ROS by FACS using the fluorescent dye DCFDA revealed that this cell death was primarily due to increased ROS accumulation triggered by PEITC-induced depletion of cellular glutathione. This aberrant increase in ROS caused mitochondrial membrane damage, as determined by biochemical analysis using Rhodamine 123, and subsequent cell death through apoptosis. Importantly, PEITC was very effective in melanoma cells, which exhibited resistance to standard anti-tumor drugs like temozolomide (TMZ) and carmustine (BCNU). Our study suggests that PEITC may be an effective anti-melanoma therapeutic agent that warrants further pre-clinical and clinical investigation. Our work is now directed towards identifying other ROS related cellular mechanisms that can be exploited to increase the therapeutic specificity and sensitivity of PEITC in melanoma cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2011-2645