Abstract
Lung cancer is the most common cause of cancer-related death in men and women. Incidence rate of lung cancer is keep increasing year after year. Lot of progress has been made in field of lung cancer therapy to prolong lifespan of patients, but it is still inadequate. In our previous study, novel alkylating agent BO-1012 in combination with arsenic trioxide shown to have very good therapeutic efficacy in lung cancer H460 Xenografted mice. Meanwhile, we also observed activation of survival and DNA repair protein molecules in cells treated with BO-1012. In further development of drug up on modification in functional group of BO-1012, we observed enhanced lethal effect of BO-1509 in lung cancer cells. To overcome activation of survival and DNA repair protein we combined BO-1509 with PI3 kinase inhibitor LY294002. Synergism being found between two drugs in several lung cancer cells like H460, CL-1-5, CL-25 and CL-83 in culture. Furtherome, alone at doses of 5 mg/kg and 10 mg/kg BO-1509 by iv for five times reduce tumor burden 50% and 70% in H460 and CL-1-5 xenografted mice respectively. But when it combined with PI3 kinase inhibitor (LY294002) 40 mg/kg injected by ip for 10 times, tumor burden reduced 85% in H460 and 86% in CL-1-5 xenografted mice. Initial finding suggests that synergism between BO-1509 and PI3 kinase inhibitor may be due to inhibitory effect of PI3 kinase on Mre11 and Nbs1 proteins of MRN complex which play important role in homologous repair pathway. Mre11 and Nbs1 protein were found to be elevated upon treated with of BO-1509 in H460 cells. PI3 kinase inhibitor also prevents BO-1509 activated nuclear localization of Rad51 in H460 and CL-1-5 cells which is confirmed by using confocal microscopy. Based on H2AX foci formation assay, half of double strand break (DSB) in cell induced by BO-1509 get repaired by 72 h, while cells treated in combination of BO-1509 with PI3 kinase inhibitor still maintain DSB damage, which may enhance the lethal effect of BO-1509 to H460 and CL-15 cell. Complete blood profile, biochemical enzyme analysis and histopathology of major organ suggest no significant toxicity in mice treated with BO-1509 alone or in combination with PI3 kinase inhibitor.
In conclusion the combination with PI3 inhibitor increases the efficacy of BO-1509 by suppressing the DNA repair and survival factor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B66.
