Abstract 3100: Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors

Abstract

Abstract Agents targeting colchicine-binding site are recognized as valuable lead compounds in the development of new anticancer drugs. Although colchicine can effectively inhibit cell proliferation, its use as an anticancer agent has not been approved by FDA due to its inherent toxicity. To develop colchicine-binding site targeting agents with low or no toxicity, we have created and examined several chalcone derivatives, from which we have identified CTR-17 and CTR-20 as promising leads. We have examined their anti-proliferative activities 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 CTR-17 and CTR-20 preferentially kill cancer cells 10-100 times over non-cancer cells. Data obtained from flow cytometry, confocal microscopy and Western blotting showed that CTR-17 and CTR-20 induced prolonged mitotic arrest prior to killing cancer cells by apoptosis. We also found that both CTR-17 and CTR-20 inhibit tubulin polymerisation and bind to purified tubulin fibers with a dissociation constant of 3.4±1.7 μM and 5.9±1.9 μM, respectively. CTR-17 competitively inhibits the binding of colchicine to tubulin with an inhibitory concentration of 8.67 μM, suggesting that CTR-17 binds to tubulin at a site close to the colchicine binding site. Molecular docking studies confirmed this binding which occurs via three hydrogen bonds and Van der Waals interactions. In our xenograft model of the human breast cancer cells, the treatment of mice with CTR-17 or CTR-20 (30 mg/kg) twice per week for 30 days effectively inhibits tumor growth. The combination of CTR compounds (15 mg/kg/week) and paclitaxel (5 mg/kg/week) increases paclitaxel's anti-tumor activity by 40-60%. Most importantly, both CTR-17 and CTR-20, when used alone or in combination with paclitaxel, showed no notable toxicity to vital organs (spleen, liver, kidney and lung). Therefore, the novel CTR-17 and CTR-20 chalcone derivatives possess substantial potential as safe and effective anticancer drugs. This project was supported in part from the funds by the Northern Ontario Heritage Funds Corporation, Northern Cancer Foundation, and The City of Greater Sudbury Development Corporation. IKL is a recipient of the Ontario Trillium Scholarship. Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Dr. Piyush Trivedi, Dr. Hoyun Lee. Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2015-3100