Abstract B151: Epithelial-to-mesenchymal transition (EMT) in resistance to the antiproliferative effects of elisidepsin (Irvalec™), a novel marine-derived depsipeptide, in colon cancer cells

Abstract

Abstract Background: Elisidepsin (PM02734) belongs to Kahalalide F family and displays antiproliferative effects as single agent and in combinations with both cytotoxic and targeted therapies. This study aimed evaluating the role of EMT in resistance to elisidepsin. Materials and Methods: Antiproliferative effects of elisidepsin were evaluated in a panel of colon (HT29, HCT116, COLO205, HCC2998), breast (MCF7, MDA-MB-435, SKBR3), ovarian (OVCAR3, IGROV1), lung (Hop62, Hop92), prostate (PC3, DU145), head&neck (SCC61, SQ20B, HEP2), and pancreatic (MiaPaCa2, CAPAN1) cancer cell lines after 72 hour exposure using MTT assay. Expression of several genes was evaluated using quantitative RT-PCR. Results: Elisidepsin displayed antiproliferative effects against cancer cells with IC50s ranging 0.4’9 µM. As previously reported, cancer cells with high mRNA levels of Erb-B3 also displayed sensitivity to elisidepsin. Consistently, we found that cancer cells displaying an epithelial phenotype, characterized by high levels of mRNA expression of E-cadherin (CDH1), were more sensitive to elisidepsin than mesenchymal cancer cells showing high mRNA and protein levels of vimentin and N-cadherin (CDH2). To further evaluate the role of EMT in resistance to elisidepsin, we studied the antiproliferative effects of elisidepsin in the epithelial colon Colo205-S cells and its derived mesenchymal counterpart Colo205-R cells characterized by the overexpression of the transcription factors SIP1, ZEB1, SNAIL, SLUG, TWIST, and TGFβ. Interestingly, Colo205-S cells were at least 8-fold more sensitive to elisidepsin than Colo205-R cells, IC50s being 0.5 and 4.0µM, respectively. To confirm the role of EMT on resistance to elisidepsin, we used another colon cancer model with inducible SNAIL expression (DLD-1TR21-hSNAIL). In this model, SNAIL induction leads to a mesenchymal phenotype that coincides with loss of aggregation and induction of invasion (EMT). In this model, more than 100-fold SNAIL increase was associated with 12 and 6-fold decrease of E-cadherin and Erb-B3 expression, respectively. Consistent with our hypothesis, we found that the cytotoxicity of elisidepsin was at least 7-fold higher in parental epithelial cells than in SNAIL-induced cells in this model. Conclusions: Sensitivity to elisidepsin correlates with high Erb-B3 and E-cadherin expressions in colon cancer cells. These data suggest that sensitivity to elisidepsin may be dependent of cancer cell differentiation, better results being observed in cancer cells retaining an epithelial phenotype. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B151.