Abstract C22: The effect of irinotecan-induced in k-Ras wild and mutant type colon cancer cell lines.

Abstract

Abstract Irinotecan (IRI) prevents DNA from unwinding by inhibition of topoisomerase [[Unable to Display Character: І]]. Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. Recent studies, those with irinotecan treatment has a synergistic effect appears. However, there is no study on the effect of the irinotecan mono-treatment. In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially kras wild and mutant type colon cancer, are not yet known. Bax protein is a key mediator of apoptosis and might be related to chemosensitivity. In this work, we evaluated the anti-tumorigenic action of these irinotecan anti-cancer agents with especially k-ras wild and mutant type colon cancer cell lines, and investigated their apoptosis-inducing effects as the potential mechanism in this process. The results show that the growth inhibitory effects of 5-fuorouracil (5-FU), Oxaliplatin(OX) produced a dose- and time dependent fashion in k-ras wild (HT29, Colo205) and mutant type (HCT116, DLD-1) colon cancer cell lines. Otherwise, irinotecan produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines. Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that IRI induces these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria, the activation of caspase9, the cleavage of PARP. But Bax protein was inactivation in k-ras wild type colon cancer cell lines. Importantly, inhibition of ERK kinase activity demonstrated that IRI-induced apoptotic pathway was regulated by the ERK signaling cascade. These data indicate that anti-cancer agent, irinotecan, promotes Bax-mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C22. Citation Format: Myoung Hee Kang, Bo Ram Kim, Sun il Lee, Jun Suk Kim, Sang Cheul Oh. The effect of irinotecan-induced in k-Ras wild and mutant type colon cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C22.