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Induction of Apoptosis by Fucoidan in Human Leukemia U937 Cells through Activation of p38 MAPK and Modulation of Bcl-2 Family
Department of Pharmacy, Pusan National University, Busan 609-735, Korea
Department of Food and Nutrition, Dongeui University, Busan 614-714, Korea
Anti-Aging Research Center & Blue-Bio Industry Regional Innovation Center, Dongeui University, Busan 614-714, Korea
Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Korea
Departments of Parasitology and Genetics, Kosin University College of Medicine, Busan 602-702, Korea
Department of Urology, Chungbuk National University College of Medicine, Cheongju 361-763, Korea
Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714, Korea
Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea
* Authors to whom correspondence should be addressed.
Received: 26 April 2013; in revised form: 30 May 2013 / Accepted: 13 June 2013 / Published: 4 July 2013
Abstract: The present study investigated possible mechanisms on the apoptosis induction of human leukemic cells by fucoidan, a sulfated polysaccharide found in marine algae. Fucoidan treatment of cells resulted in inhibition of growth and induction of apoptosis, as measured by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl-tetrazolium (MTT) assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. The increase in apoptosis was associated with the proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria, release of cytochrome c from mitochondria to cytosol, and loss of mitochondria membrane potential (MMP) in U937 cells. However, apoptosis induced by fucoidan was attenuated by caspase inhibitors, indicating that fucoidan-induced apoptosis was dependent on the activation of caspases. Furthermore, fucoidan treatment effectively activated the p38 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitor, SB203580, and significantly reduced fucoidan-induced apoptosis through inhibition of Bax translocation and caspases activation, suggesting that the activation of p38 MAPK may play a key role in fucoidan-induced apoptosis. In addition, the authors found fucoidan-induced significantly attenuated in Bcl-2 overexpressing U937 cells, and pretreatment with fucoidan and HA 14-1, a small-molecule Bcl-2 inhibitor, markedly increased fucoidan-mediated apoptosis in Bcl-2 overexpressing U937 cells. Our findings imply that we may attribute some of the biological functions of p38 MAPK and Bcl-2 to their ability to inhibit fucoidan-induced apoptosis.
Keywords: fucoidan; leukemic cells; apoptosis; p38 MAPK; Bcl-2
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Park, H.S.; Hwang, H.J.; Kim, G.-Y.; Cha, H.-J.; Kim, W.-J.; Kim, N.D.; Yoo, Y.H.; Choi, Y.H. Induction of Apoptosis by Fucoidan in Human Leukemia U937 Cells through Activation of p38 MAPK and Modulation of Bcl-2 Family. Mar. Drugs 2013, 11, 2347-2364.
Park HS, Hwang HJ, Kim G-Y, Cha H-J, Kim W-J, Kim ND, Yoo YH, Choi YH. Induction of Apoptosis by Fucoidan in Human Leukemia U937 Cells through Activation of p38 MAPK and Modulation of Bcl-2 Family. Marine Drugs. 2013; 11(7):2347-2364.
Park, Hyun S.; Hwang, Hye J.; Kim, Gi-Young; Cha, Hee-Jae; Kim, Wun-Jae; Kim, Nam D.; Yoo, Young H.; Choi, Yung H. 2013. "Induction of Apoptosis by Fucoidan in Human Leukemia U937 Cells through Activation of p38 MAPK and Modulation of Bcl-2 Family." Mar. Drugs 11, no. 7: 2347-2364.