Abstract 1950: The effects of combination treatment of NO-donor and MEK inhibitor on proliferation and invasion of cancer cell lines

Abstract

Abstract [Background] Nitric oxide (NO) possesses cytostatic and cytotoxic actions on cancer cells. MAPK and PI3K/Akt signaling pathways, those exist downstream of IGF-IR and EGFR, are two major pathways of oncogenic transformation and tumor maintenance in many kinds of cancer cells. Several studies demonstrated that NO inhibits PI3K/Akt pathway, on the other hand, NO enhances activates MAPK pathway by means of activation of H- and N-Ras. MEK inhibitor blocks MAPK pathway. Hence, we hypothesized that combination of NO-donor and MEK inhibitor inhibits proliferation and invasion of cancer cells in comparison with NO-donor or MEK inhibitor alone. [Methods and Results] We assessed effects of combination of GSNO (NO-donor) and U0126 (MEK inhibitor) on phosphorylation of Akt, and Erk1/2 after stimulation of IGF-I and EGF using Western blotting analyses. Combination of GSNO (500 μM) and U0126 (10 μM) down-regulates phosphorylation of Akt, and Erk1/2 after stimulation of IGF-I (25 nM) and EGF (100 ng/ml) more strongly in comparison with GSNO or U0126 alone in MIAPaCa-2 cells and HCT-116 cells. Combination of GSNO (200, 500 μM) and U0126 (10 μM) also inhibited cell proliferation of MIAPaCa-2 cells and HCT-116 cells more strongly in comparison with NO-donor or MEK inhibitor alone. Furthermore, combination of these compounds inhibited invasion of MIAPaCa-2 cells and HCT-116 cells more strongly in comparison with NO-donor or MEK inhibitor alone in vitro. [Discussion] Recent reports revealed that inhibition of PI3K/Akt or MAPK pathway alone was insufficient to robustly induce tumor shrinkage. It indicated that a feedback pathway between intracellular signalings might be up-regulated, if one main signaling pathway was inhibited. Concomitant inhibition of both PI3K/Akt and MAPK pathway by means of NO-donor and MEK inhibitor could inhibit not only cell growth but also invasion to suppress feedback loops. These results suggest that the combination treatment of NO-donor and MEK inhibitor may be useful for cancer therapy. 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 1950. doi:10.1158/1538-7445.AM2011-1950