Sequential treatment with celecoxib and bortezomib enhances the ER stress-mediated autophagy-associated cell death of colon cancer cells

Treatment with celecoxib and bortezomib as single chemotherapeutic agents reduces the viability and proliferation of colorectal cancer cells. The use of these agents in combination with other chemotherapeutic agents is usually associated with adverse effects. In the present study, a combination of celecoxib and bortezomib was investigated for potential synergistic effects in colon cancer cells. The sequential exposure to celecoxib with bortezomib synergistically induced apoptotic death in human colon cancer cells compared with groups treated with a single drug or other drug combinations. c-Jun N-terminal kinase/p38-mitogen-activated protein kinase-induced endoplasmic reticulum (ER) stress through serial exposure to celecoxib and bortezomib may have induced the intracellular Ca(2+) release, leading to the generation of autophagosomes in p53-expressing HCT-116 cells. Targeted inhibition of p53 activity or ER stress or treatment with the Ca(2+)-chelating agent BAPTA-AM suppressed the ER stress-mediated Ca(2+) release and apoptosis. Although p53(−/−) HCT-116 cells were less sensitive to sequential treatment with celecoxib and bortezomib, co-localization of autophagosomes was detected in the absence of CCAAT-enhancer-binding protein homologous protein expression. Treatment of p53(−/−) HCT-116 cells with BAPTA-AM did not inhibit apoptosis following serial treatment with celecoxib and bortezomib. These results suggest that the order of drug administration is important in treating cancer and that the sequential treatment with celecoxib and bortezomib enhances the ER stress-mediated autophagy-associated cell death of colon cancer cells, regardless of p53 expression.