Acetyl-keto-β-boswellic acid down-regulates G1 phase cyclin/CDKs and inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells

2073 Accumulating evidences showed that boswellic acid might be a potential chemopreventive and chemotherapeutic drug in colon cancer, although the molecular mechanism was still not clear. In the present study, we investigated the mechanisms of the growth inhibitory effect of acetyl-keto-boswellic acid (AKBA) in colon cancer cells. AKBA inhibited cellular growth in a time and dose-dependent manner in HCT-116 cells. The growth inhibitory effect of AKBA was not cell type-specific as AKBA also inhibited cellular growth in both HT-29 and LS174T colon cancer cells. Cell cycle analysis by flow cytometry showed that cells were arrested at G1/S phase after AKBA treatment. To study the molecular mechanism of the growth inhibitory effect of AKBA, expressions of cyclins and cyclin-dependent kinases (CDKs) controlling the G1-S phase transition were assayed using western blot. Results showed that cyclins and CDKs, including cyclin D1 and E, CDK2 and CDK4, were significantly decreased in AKBA treated cells. Also, AKBA treatment up-regulated the expression of CDK inhibitors like p21 and p27, another group of factors controlling the G1-S phase transition. Further studies in p21-/- HCT-116 cells found that the growth inhibitory effect of AKBA was dependent on the expression of p21, not p53. Colon cancer cells lacking the expression of p21 were sensitized to the apoptotic effect of AKBA, instead of being checked at G1/S transition. In conclusion, we found that AKBA down-regulated G1 phase cyclins and CDKs and up-regulated CDK inhibitors in colon cancer cells. The G1/S arrest induced by AKBA was dependent on p21.