Superior antimitogenic and chemosensitization activities of the combination treatment of the histone deacetylase inhibitor apicidin and proteasome inhibitors on human colorectal cancer cells.

Despite the effectiveness of histone deacetylase inhibitors, proteasome inhibitors and cytotoxic drugs on human cancers, none of these types of treatments by themselves has been sufficient to eradicate the disease. The combination of different modalities may hold enormous potential for eliciting therapeutic results. In the current study, we examined the effects of treatment with the histone deacetylase inhibitor (HDACI) apicidin (APC) in combination with proteasome inhibitors on human colorectal cancer cells. The molecular mechanisms of the combined treatments and their potential to sensitize colorectal cancer cells to chemotherapies were also investigated. Cancer cells were exposed to the agents alone and in combination, and cell growth inhibition was determined by MTT and colony formation assays. HDAC, proteasome and NF-κB activities as well as reactive oxygen species (ROS) were monitored. Cell cycle perturbation and induction of apoptosis were assessed by flow cytometry. The expression of cell cycle/apoptosis- and cytoprotective/stress-related genes was determined by quantitative PCR and EIA, respectively. The potentiation of cancer cell sensitivity to chemotherapies upon APC/PI combination treatment was also studied. The combination of APC and MG132, PI-1 or epoxomicin potently inhibited cancer cell growth, disrupted the cell cycle, induced apoptosis, decreased NF-κB activity and increased ROS production. These events were accompanied by the altered expression of genes associated with the cell cycle, apoptosis and cytoprotection/stress regulation. The combination treatment markedly enhanced the chemosensitivity of colorectal cancer cells (50-3.7 x 10(4)-fold) in a drug-, APC/PI combination- and colorectal cancer subtype-dependent manner. The results of this study have implications for the development of com-binatorial treatments that include HDACIs, PIs and conventional chemotherapeutic drugs, suggesting a potential therapeutic synergy with general applicability to various types of cancers.