carboxycinnamic-acid-bishydroxamide and Colonic-Neoplasms

We investigated whether the histone deacetylase inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and a bicyclic depsipeptide, FK228, can enhance the anticancer effect of the proteasome inhibitors PSI and PS-341 in gastrointestinal carcinoma cells.. The anticancer effect of CBHA or FK228 and PSI or PS-341 was evaluated by cell death, caspase-3 activity, externalization of phosphatidylserine and DNA fragmentation, and colony formation assay. Expression of apoptosis-related molecules and cell cycle regulatory molecules, as well as phosphorylation of p38 were investigated by immunoblots. Generation of reactive oxygen species (ROS) was detected by intracellular oxidation of 5- (and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate.. CBHA or FK228 plus PSI or PS-341 synergistically induced apoptosis in human colonic DLD-1 and gastric MKN45 carcinoma cell lines. CBHA or FK228, but not 5-fluorouracil, plus PS-341 strongly decreased plating efficiency of DLD-1 cells. FK228 elicited ROS generation, and the free radical scavenger l-N-acetylcysteine inhibited the synergistic anticancer effect of combined therapy. In addition, l-N-acetylcysteine inhibited the combined therapy-mediated elevation of a proapoptotic BH3-only protein Bim expression, phosphorylation of H2AX, and accumulation of 8-hydroxydeoxyguanosine.. FK228 or CBHA and PSI or PS-341 synergistically induce apoptosis in DLD-1 and MKN45 cells depending on ROS-mediated signals. Our data suggest that a combination of FK228 or CBHA with PSI or PS-341 may be a valuable therapy against gastrointestinal adenocarcinoma cells.

Topics: Adenocarcinoma; Annexin A5; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Boronic Acids; Bortezomib; Caspase 3; Caspases; Cell Line, Tumor; Cinnamates; Colonic Neoplasms; Depsipeptides; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Free Radicals; Gastrointestinal Neoplasms; Histones; Humans; Microscopy, Confocal; Oligopeptides; Oxygen; Phosphorylation; Proteasome Inhibitors; Pyrazines; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors