Abstract 701: Characterization of two novel quinoline derivatives that induce apoptosis in a cancer-specific manner.

Abstract

Abstract Many quinoline-based compounds possess pharmacological properties that are beneficial for the control of various human diseases, including microbial infections, inflammatory-related disorders, cardiovascular conditions, and cancer. The anticancer activities of quinoline compounds are often rendered by their property of inhibiting protein kinases, proteasome activity, tubulin polymerization/depolymerization and DNA repair. To further improve the efficacy and specificity, we created and characterized several quinoline derivatives, which led us to identify CTRI-17 and CTRI-20 as promising leads. We examined their anti-proliferative properties using three human breast cancer cell lines (MDA-MB-468, MDA-MB-231 and MCF-7) and two matching non-cancer breast cell lines (184B5 and MCF10A). In addition, we also examined their efficacy using one leukemic cell line (K-562) and one cervical cell line (HeLa). Data from this study showed that the IC50 values of CTRI-17 and CTRI-20 were 0.1-0.3 μM and 1.2-2.4 μM ranges on cancer and non-cancer cell lines, respectively. Thus, both CTRI-17 and CTRI-20 killed cancer cells 10-20 times more effectively than non-cancer cells. This differential cell killing effects on cancer and non-cancer cells is a highly desirable property for potential anticancer therapeutics. We further found that cancer cells treated with the two compounds resulted in increases of pro-apoptotic proteins such as p53 and Bax, and decreases of anti-apoptotic proteins such as Bcl-2 and survivin. Our data obtained from flow cytometry and confocal microscopy showed that CTRI-17 and CTRI-20 induced prolonged cell cycle arrest at G2/M phase prior to causing apoptosis in cancer cells. However, the two compounds neither induced substantial cell cycle arrest nor caused high levels of apoptosis in non-cancer cells at the same drug concentration. We are currently in the process of determining the detailed functional mechanisms of CTRI-17 and CTRI-20. Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Yi-Fang Lee, Hoyun Lee, Piyush Trivedi. Characterization of two novel quinoline derivatives that induce apoptosis in a cancer-specific manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 701. doi:10.1158/1538-7445.AM2013-701