Histone deacetylase inhibitors (HDACIs) exhibit modest results as single agents in preclinical and clinical studies against solid
tumors; they often fall short and activate
nuclear factor kappa-B (NFκB). Co-administration of HDACI with
proteasome inhibitors (PIs), which interrupt NFκB pathways, may enhance HDACI-lethality. The goal of this study was to determine whether PIs could potentiate HDACI,
scriptaid (SCP)-mediated lethality, to unravel the associated mechanisms and to assess the effects of the combined inhibition of HDAC and
proteasome on
chemotherapy response in human
colorectal cancer cells.
Cancer cells were exposed to agents alone or in combination; cell growth inhibition was determined by MTT and colony formation assays. HDAC-,
proteasome-, NFκB-activities, and
reactive oxygen species (ROS) were quantified. Induction of apoptosis and cell cycle alterations were monitored by flow cytometry. Expression of cell cycle/apoptosis and cytoprotective/stress-related genes was determined by real-time qRT-PCR and EIA, respectively. Potentiation of
cancer cell sensitivity to
chemotherapies by SCP/PIs was also evaluated. SCP and PIs:
MG132, PI-1, or
epoxomicin interact synergistically to potently inhibit
cancer cell growth, alter cell cycle, induce apoptosis, reduce NFκB activity, and increase ROS generation. These events are associated with multiple perturbations in the expression of cell cycle, apoptosis, cytoprotective, and stress-related genes. Co-administration of SCP and PIs strikingly increases the chemosensitivity of
cancer cells (122-2 × 10(5)-fold) in a
drug and SCP/PIs-dependent manner. This combination regimen markedly reduced the doses of
chemotherapies with potent anticancer effects and less toxicity. A strategy combining HDAC/
proteasome inhibition with
chemotherapies warrants further investigation in
colorectal cancer.