Abstract 3805: Identification of a distinctive pattern of lipid composition in Irvalec® resistant tumor cells

Abstract

Abstract Irvalec® is a marine derived synthetic depsipeptide showing cytotoxic activity against a wide diversity of tumor cells both in vitro and in vivo. The compound is currently undergoing Phase II clinical studies in patients with solid tumors. The existing data on the mechanism of action of Irvalec® indicate that the compound inserts and self-organize in the plasma membrane of tumor cells, rapidly inducing loss of membrane integrity and cell permeabilization, giving rise to a fast and dramatic necrotic death. By continuous exposure of human colon carcinoma HCT-116 cells to stepwise increasing concentratrions of Irvalec®, a resistant subclone of the cell line was established, named HCT-116-Irv. In dose-response cytotoxicity assays, HCT-116-Irv cells showed a GI50 value >50 μM, representing a specific resistance index to the compound greater than 10.8 as compared to their wt counterpart. The resistant cells did not show any of the morphological and physiological responses to Irvalec® observed in parental cells and no overexpression of Pgp efflux pump or significant cross-resistance to other antitumoral drugs was detected. Due to the presumably direct effect of Irvalec® on the cell membrane, we searched for possible changes in the lipid composition of the resistant cells, acquired during the process of resistance development. After fractionation of the lipid extracts using thin layer cromatography (TLC), two differential fractions, that were completely absent in the resistant cells as compared to wt cells, were identified and purified. Interestingly, one of these fractions, named F4, was found to be able to interact with a biotinilated derivative of Irvalec®, using a standard overlay assay. These results suggested that the lipid composition could be directly related to the sensitivity of tumor cells to Irvalec®. Efforts are now focused on the chemical characterization of the selected lipid fraction and its putative biological role mediating the cytotoxic response to Irvalec®. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3805. doi:1538-7445.AM2012-3805