title: Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells.
abstract: CDDO-Me, an oleanane synthetic triterpenoid has shown strong antitumorigeic activity towards diverse cancer cell types including colorectal cancer cells. In the present study, we investigated the role of free radicals in the growth inhibitory and apoptosis-inducing activity of CDDO-Me in colorectal cancer cells lines. Results demonstrated that CDDO-Me potently inhibited the growth of colorectal cancer cells and pretreatment of cancer cells with small-molecule antioxidant N-acetylcysteine (NAC) completely blocked the growth inhibitory activity of CDDO-Me. CDDO-Me caused the generation of reactive oxygen species, which was inhibited by NAC and mitochondrial chain 1 complex inhibitors DPI and rotenone. CDDO-Me induced apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization and NAC blocked the activation of these apoptosis related processes. Furthermore, induction of apoptosis by CDDO-Me was associated with the inhibition of antiapoptotic/ prosurvival Akt, mTOR and NF-kappaB signaling proteins and the inhibition of these signaling molecules was blocked by NAG. Together these studies provided evidence that CDDO-Me is a potent anticancer agent, which imparts growth inhibition and apoptosis in colorectal cancer cells through the generation of free radicals.
authors.affiliation: Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gao
authors.forename: Dorrah
authors.initials: D
authors.lastname: Deeb
authors.forename: Patricia
authors.initials: P
authors.lastname: Liu
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Syed
authors.initials: S
authors.lastname: Arbab-Ali
authors.forename: Scott A
authors.initials: SA
authors.lastname: Dulchavsky
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gautam
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D005609:Free Radicals; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D000111:Acetylcysteine