Nature Medicine
1, 1046 - 1051 (1995)
doi:10.1038/nm1095-1046
Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosisEmily Pisha1, Heebyung Chai1, Ik-Soo Lee1, Tangai E. Chagwedera2, Norman R. Farnsworth1, Geoffrey A. Cordell1, Christopher W.W. Beecher1, Harry H.S. Fong1, A. Douglas Kinghorn1, Daniel M. Brown3, 5, Mansukh C. Wani3, Monroe E. Wall3, Tina J. Hieken4, Tapas K. Das Gupta4
& John M. Pezzuto1, 4, 6
1Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA
2Department of Pharmacy, University of Zimbabwe, Harare, Zimbabwe
3Chemistry and Life Sciences Division, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA
4Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
5Present address: Bristol-Myers Squibb - PRI, Natural Products -114, Wallingford, Connecticut 06492, USA
6Correspondence should be addressed to J.M.P. As a result of bioassay−guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma−specific cytotoxic agent. In follow−up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preciinicai development for the treatment or prevention of malignant melanoma.
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