Abstract 5512: Mechanisms of inhibition of cancer cell growth and metastasis by novel small molecule compounds.

Abstract

Abstract The molecular complexity of cancers and therapy-associated side effects often limit effectiveness of many therapies, and warrant development of new agents for specific molecular targets while minimizing the off-target effects. Thus, our goal is to develop novel, safer and effective anti-cancer therapies on the basis of cell growth and survival inhibiting functions of an apoptosis regulatory protein, termed CARP-1. CARP-1 was identified by us as a novel target of select chemotherapy (adriamycin, etoposide, or Iressa)-dependent human breast cancer cell growth suppression. By conducting the high-throughput screening of chemical libraries, we identified a number of novel, small molecule compounds called CARP-1 Functional Mimetics (CFMs). MTT assay results showed that CFMs, as well as quinazoline analogues of CFMs, inhibited growth of a variety of cancer cells, including the drug-resistant breast cancer cell line MDA-MB 468, without affecting growth of immortalized mammary epithelial cells. Results of MTT assay indicated also that CFM-4 (1(2-chlorobenzyl)-5′-phenyl-3′H-spiro[indoline-3,2′-[1,3,4]thiadiazol]-2-one) was the most potent one. CFMs suppressed cancer cell growth in part by stimulating CARP-1 levels and promoting cell cycle arrest and apoptosis. RT-PCR assay results revealed that CFM-4 induced the extrinsic pathway of apoptosis via upregulation of TRAIL receptors, caspase-8 and caspase-3 which can then cleave multiple cellular proteins, leading to cancer cell death. Cancer-related deaths are often due to spread of cancers to other organ sites (metastasis) that involves invasion and movement of cancer cells through the nearby normal tissue and the lymph and blood vessels to reach other tissues to form secondary tumors. Here we also demonstrate that CFMs impact biological properties of cancer cells by inhibiting their movement and invasion through the membranes coated with the extra-cellular matrix. CFMs also inhibited abilities of cancer cells to grow as colonies in soft-agar. These proof-of-concept studies suggest that CFMs could induce cancer cell apoptosis and effectively inhibit migration and tumor-forming abilities of cancer cells. Thus CFMs or their analogues have potential as anti-cancer agents to target cancer cell proliferation, survival, migration, invasion and metastasis, and provide a strong basis for their development as anti-cancer agents. Citation Format: Abdelkader E. Ashour, Vino T. Cheryan, Shazia Jamal, Ahmed M. Alafeefy, Khairy M. Zoheir, Adel R. Abdallah, Arun K. Rishi. Mechanisms of inhibition of cancer cell growth and metastasis by novel small molecule compounds. [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 5512. doi:10.1158/1538-7445.AM2013-5512