title: The antidiabetic compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from Averrhoa carambola L., demonstrates significant antitumor potential against human breast cancer cells.
abstract: 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione found in the roots of Averrhoa carambola L., commonly known as starfruit. Researchers have shown that DMDD has significant therapeutic potential for the treatment of diabetes; however, the effects of DMDD on human cancers have never been reported. We investigated the cytotoxic effects of DMDD against human breast, lung and bone cancer cells in vitro and further examined the molecular mechanisms of DMDD-induced apoptosis in human breast cancer cells. DMDD suppressed the growth of breast carcinoma cells, but not normal mammary epithelial cells, via induction of G1 phase cell cycle arrest, oxidative stress and apoptosis. DMDD increased the level of intracellular reactive oxygen species (ROS) and DMDD-induced ROS generation was found to be associated with the mitochondrial activity. The cytotoxicity that was induced by DMDD was attenuated by co-treatment with the antioxidant N-acetyl-L-cysteine (NAC). DMDD-induced cell apoptosis involved the activation of both the intrinsic mitochondrial pathway and the extrinsic receptor pathway. In addition, DMDD inhibited the canonical NF-κB signaling pathway at all steps, including TNF-α production, phosphorylation of NF-κB p65 and IκBα, as well as TNF-α activated NF-κB p65 nuclear translocation.Collectively, our studies indicate that DMDD has significant potential as a safe and efficient therapeutic agent for the treatment of breast cancer.
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, PR China.
authors.forename: Renbin
authors.initials: R
authors.lastname: Huang
authors.affiliation: Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Hyo Sim
authors.initials: HS
authors.lastname: Park
authors.affiliation: Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, PR China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Nadin Marwan
authors.initials: NM
authors.lastname: Almosnid
authors.affiliation: Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Uma D
authors.initials: UD
authors.lastname: Chippada-Venkata
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Najlaa Abdulrhman
authors.initials: NA
authors.lastname: Hosain
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vick
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Farone
authors.affiliation: Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Altman
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D065826:Averrhoa / Q000737:chemistry*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D053138:Cyclohexenes / Q000737:chemistry*; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C581182:2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; D000970:Antineoplastic Agents; D000975:Antioxidants; D053138:Cyclohexenes; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D020169:Caspases; D000111:Acetylcysteine
keywords: NF-κB; antitumor; apoptosis; cell cycle; reactive oxygen species