Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions
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Yang Jiao1,2, Bethany N. Hannafon1, Roy R. Zhang1, Kar-Ming Fung1,3, Wei-Qun Ding1,3
1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
2School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, P.R. China
3Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
Wei-Qun Ding, email: email@example.com
Keywords: docosahexaenoic acid, disulfiram, oxidative stress, nuclear factor (erythroid-derived 2)-like 2, cancer stem cell
Received: June 17, 2016 Accepted: December 16, 2016 Published: January 17, 2017
We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.
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