Sequential administration of camptothecin sensitizes human colon cancer HCT116 cells to paclitaxel via p21∨Cip1/WAF1

Colorectal cancer is the third leading cause of cancer-related death in Western countries. Chemotherapeutic agents with different mechanisms of action have shown an increase in cure rates. In the present study, we investigated the effect of a combination of low concentration of paclitaxel (taxol, 5 nM) and topoisomerase 1 inhibitor camptothecin (CPT) on HCT116 colon cancer cells. Although the viability of cells treated with taxol alone was similar to that of control cells, sequential treatment with taxol and CPT exhibited high cytotoxicity. However, the opposite sequence of treatment did not exert cytotoxic effects on HCT116 cells. This enhanced cytotoxicity of the sequential combination therapy was the result of mitotic arrest, which increased the level of p21∨Cip1/WAF1 through the p38 mitogen-activated protein kinase (MAPK) pathway. Knockdown by p21∨Cip1/WAF1 siRNA or treatment with a p38 inhibitor reduced the viability of cells sequentially exposed to taxol and CPT. Taken together, a low taxol concentration in combination with CPT induced mitotic arrest in HCT116 cells, leading to synergistic cell death through enhanced expression of p21∨Cip1/WAF1 and p38 MAPK pathway. Therefore, taxol could play a role as a sensitizer of CPT in colon cancer cells.