Enhancement of paclitaxel-induced apoptosis by inhibition of mitogen-activated protein kinase pathway in colon cancer cells

Resistance to chemotherapy represents a major obstacle to improving the survival of patients with colorectal cancer. In this study, the inhibition of the mitogen-activated protein kinase (MAPK) pathway was demonstrated to markedly enhance the apoptosis of colon cancer cells induced by paclitaxel, one of the key chemotherapeutic drugs widely used to treat various types of cancer. The treatment of the colon cancer cell lines SW480 and DLD-1 with paclitaxel resulted in increased activation of the MAPK pathway, which was blocked by PD98059, a MEK inhibitor. In both cell lines, MAPK inhibition by PD98059 led to a dramatic enhancement of the paclitaxel-induced apoptosis, as determined by cell cycle analysis and Hoechst 33342 staining, although the inhibitor alone did not affect apoptosis. This effect was restricted to paclitaxel since PD98059 did not alter the sensitivity to other drugs, including 5-fluorouracil (5-FU) and camptothecin (CPT). Importantly, selective blockage of the MAPK pathway by small interfering RNA (siRNA) also increased the apoptotic cell death induced by paclitaxel. These findings highlight the importance of the MAPK pathway in paclitaxel-induced apoptosis and suggest that a combined treatment with paclitaxel and MEK inhibitors could be an attractive therapeutic strategy against colon cancer.