Synergistic induction of apoptosis and chemosensitization of human colorectal cancer cells by histone deacetylase inhibitor, scriptaid, and proteasome inhibitors: potential mechanisms of action

Abstract

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.

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

“…Single treatment with the tested proteasome inhibitors (MG132, PI-1 and EPM) gave results consistent with those recently reported by Abaza et al (22). Treatment of SW1116 cells with MG132 resulted in a marked accumulation of the cancer cells in S-phase (57 vs. 25.5% for UT) and a decrease in cells in the G 1 /G 0 phase (25.5 vs. 40.3% for UT) and G 2 /M phase (17.4 vs. 18% for UT) (22). The combined treatment of APC with G132 arrested the cancer cells in the G 1 /G 0 phase (51.4 vs. 40.3% for UT) and S-phase (44.9 vs. 41.5% for UT), and there was a decrease in the G 2 /M phase (3.5% vs. 18% for UT).…”

Prolonged Proteasome Inhibition Cyclically Upregulates Oct3/4 and Nanog Gene Expression, but Reduces Induced Pluripotent Stem Cell Colony Formation

“…There is extensive evidence that proteasome activity plays a role in many of these processes (Naujokat and Saric, 2007), including studies indicating that combinatorial use of proteasome and HDAC inhibitors acts synergistically to inhibit proliferation (Abaza et al, 2012;Heider et al, 2009). This suggests that reversible inhibition of proteasome activity by the well-characterized peptide-based proteasome inhibitors may represent an additional approach to regulate reprogramming.…”

Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators

“…Silencing of class I HDAC expression or treatment with HDAC inhibitors shows strong antiproliferative effects and can promote apoptosis (7, 49–51). HDAC inhibition also sensitizes tumor cells to ionizing radiation and chemotherapy (52, 53). Thus, HDAC1 and HDAC2 may be the key regulators for colon cancer growth and targets for colon cancer treatment.…”