title: 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.
authors.affiliation: Molecular Biology Program, Department of Biological Sciences, College of Science, Kuwait University, PO Box 5969, Safat 13060, State of Kuwait. abazams@yahoo.com
authors.forename: M S I
authors.initials: MS
authors.lastname: Abaza
authors.forename: A M
authors.initials: AM
authors.lastname: Bahman
authors.forename: R J
authors.initials: RJ
authors.lastname: Al-Attiyah
authors.forename: A M
authors.initials: AM
authors.lastname: Kollamparambil
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C410733:scriptaid