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.