The antidiabetic compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from<i>averrhoa carambola</i>L., demonstrates significant antitumor potential against human breast cancer cells

Abstract

// Ying Gao 1 , Renbin Huang 2 , Yixuan Gong 3 , Hyo Sim Park 1 , Qingwei Wen 2 , Nadin Marwan Almosnid 1 , Uma D. Chippada-Venkata 3 , Najlaa Abdulrhman Hosain 1 , Eric Vick 1 , Anthony Farone 1 and Elliot Altman 1 1 Tennessee Center for Botanical Medicine Research and the Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee, USA 2 Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, PR China 3 Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA Correspondence to: Ying Gao, email: // Keywords : antitumor, apoptosis, cell cycle, reactive oxygen species, NF-&kappa;B Received : April 10, 2015 Accepted : May 31, 2015 Published : June 15, 2015 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-&kappa;B signaling pathway at all steps, including TNF-&alpha; production, phosphorylation of NF-&kappa;B p65 and I&kappa;B&alpha;, as well as TNF-&alpha; activated NF-&kappa;B 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.