Antitumor Effect Of Agm 130 (5 '-Oh-5-Nitro-Indirubin Oxime), A Cyclin-Dependent Kinase Inhibitor In Colorectal Cancer Cells

The AGM 130 (5’-OH-5-nitro-Indirubin oxime) compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and used in traditional Chinese medicine. AGM 130 can inhibit the proliferation of a variety cells by arresting the cell in the G2/M phase of the cell cycle, it is a cyclin-dependent kinase (CDK) inhibitor that has anti-proliferative activity and apoptotic effects on cancer cells. AGM 130 has improved water solubility compared to Indirubin, however still displays a low solubility in biologic fluids and a poor bioavailability. This poor water solubility limits the clinical application of AGM 130 to treat cancer. In this study, we decided to develop and evaluate a SNEDDS (self-nanoemulsifying drug delivery systems) formulation containing AGM130 for improving its solubility, dissolution rate, and bioavailability. To check the anti-proliferative effect of the AGM 130 compound on colon cancer cell line, we performed the MTT assay with the CT-26 cancer cell. We also performed cell cycle analysis, apoptotic assays and western blotting. The CT-26 cell bearing mice were treated intraperitoneally with AGM 130 loaded PPG-cRGD, 5-fluorouracil (5-FU) or AGM 130 loaded PPG-cRGD combined with 5-FU. We measured tumor volume and tumor progression of each groups. In vitro, AGM 130 showed significant anti-proliferative activity in CT-26 cell (IC 50, 1.9 μM). Cells treated with AGM 130 showed G2/M cell cycle arrest and also induced apoptosis compared to untreated cells. The western blotting analysis showed that AGM 130 inhibited CKD1/cyclin B1 and also CKD2/cyclin E. The greatest tumor regression (percentage tumor growth inhibition) was observed in the group treated with AGM 130 loaded PPG-cRGD combined with 5-FU. When 5-FU was administrated alone, the anti-tumor effect was inferior to the group treated with AGM 130 loaded PPG-cRGD alone. These results suggest that intraperitoneal administration of AGM 130 loaded PPG-cRGD inhibits tumor progression in a mouse colon cancer. Thus, AGM 130, a cyclin-dependent kinase inhibitors may provide a new therapeutic approach in the treatment of colon cancer. Citation Format: Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Myung-Sook Park, Hyo-Jeong Yun, Ji-Hee Lee, Sang-Hee Cho, Ik-Joo Chung. Antitumor effect of AGM 130 (5’-OH-5-nitro-Indirubin oxime), a cyclin-dependent kinase inhibitor in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2834.