Abstract B259: Novel indolizino[6,7-b]indoles suppress the growth of human non-small cell lung cancer cells in xenografted and orthotopic mouse models via induction of DNA crosslinks and inhibition of topoisomerase I and II.

Abstract

Abstract Non-small cell lung cancer (NSCLC) remains a global health problem due to the limited therapeutic responses and drug resistance. We have previously demonstrated that indolizino[6,7-b]indoles are potent antitumor agents with DNA cross-linking and topoisomerase I and II inhibition activities (JMC, 56: 1544-1563, 2013). The present study explores its therapeutic activity against NSCLC. Our results showed that BO-1922 and BO-1978, the selected derivatives of indolizino[6,7-b]indoles, effectively repressed the cell growth of several NSCLC lines, including as H460 (KRAS mutation), H1299 (TP53 deficient), A549 (KRAS mutation), CL141T (TP53 mutation), PC9 (EGFR mutation), PC9/gef B4 (EGFR mutation and acquired resistant to TKI), CL100 (EGFR mutation), and CL97 (EGFR mutation and acquired resistant to TKI). Using mouse xenograft models, we found that BO-1922 and BO-1978 could significantly suppress the tumor growth of H460, PC9, and PC9/gef B4 in mice. Furthermore, we demonstrated that these 2 compounds could remarkably inhibit the growth of CL1-5/GFP-Luciferase cells in orthotopic lung cancer model. In addition, we performed preclinical toxicity studies. Accordingly, the LD50 of BO-1922 and BO-1978 to ICR mice are 77.4 and 93.7 mg/kg, respectively. Based on blood cell counts, blood biochemistry, histopathological examination of major organs, BO-1922 and BO-1978 did not cause obvious toxicity at the doses of 20 and 40 mg/kg on day 2 and 14 after injections. Taken together, our present study revealed that BO-1922 and BO-1978 are highly prospective leads for treatment of NSCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B259. Citation Format: Chi-Wei Chen, Yi-Fan Chen, Shu-Hsin Chao, Satishkumar Tala, Tsann-Long Su, Te-Chang Lee. Novel indolizino[6,7-b]indoles suppress the growth of human non-small cell lung cancer cells in xenografted and orthotopic mouse models via induction of DNA crosslinks and inhibition of topoisomerase I and II. [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 B259.