Int J Biol Sci 2013; 9(4):403-411. doi:10.7150/ijbs.5806
A Novel Aurora-A Inhibitor, BPR1K0609S1, Sensitizes Colorectal Tumor cells to 5-Fluorofracil (5-FU) Treatment
1. Department of Medicine, NUHS, Pritzker School of Medicine, The University of Chicago, Evanston, USA.
2. Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes, Miaoli, Taiwan 305.
3. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, USA.
Small synthetic compounds have been implicated in treatment of human cancers. We have synthesized a small compound, BPR1K0609S1 (hereafter, BP), which inhibits Aurora-A kinase. In the present study, we studied the mechanism of BP suppression of tumorigenesis induced by Aurora-A. Given our previous results that inactivation of p53 accelerates MMTV-Aurora-A-mediated tumorigenesis in vivo, we studied the roles of p53 pathway using the isogenic human colon carcinoma cell lines of HCT116, in which p53, Puma, Bax, p21 or Chk2 is deleted. When these isogenic cell lines are treated with BP for 48 h, accumulation of G2M phase and aneuploidy are commonly observed, and HCT116 p21(-) cells show increase in apoptosis. In xenograft assay, s.c. injection of BP efficiently inhibits tumorigenesis of HCT116 deficient for Chk2 or p21. Re-transplantation of BP-resistant tumors indicates that these resistant cells do not acquire advanced tumor growth. Significantly, 5-FU (5-fluorouracil) treatment further induces apoptosis of BP-resistant HCT116 deficient for Chk2 or Puma. These results demonstrate that p21 deficiency enhances BP-mediated suppression of tumor growth, and that BP and 5-FU can collaborate for tumor regression.
Keywords: Aurora-A, kinase inhibitors, mice xenograft, cell cycle, apoptosis
Shionome Y, Lin WH, Shiao HY, Hsieh HP, Hsu JTA, Ouchi T. A Novel Aurora-A Inhibitor, BPR1K0609S1, Sensitizes Colorectal Tumor cells to 5-Fluorofracil (5-FU) Treatment. Int J Biol Sci 2013; 9(4):403-411. doi:10.7150/ijbs.5806. Available from http://www.ijbs.com/v09p0403.htm