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Blood, 1 August 2008, Vol. 112, No. 3, pp. 760-769. Prepublished online as a Blood First Edition Paper on May 23, 2008; DOI 10.1182/blood-2008-02-142687. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-02-142687v1 112/3/760    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mao, X. Articles by Schimmer, A. D Search for Related Content PubMed PubMed Citation Articles by Mao, X. Articles by Schimmer, A. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 28, 2008 Accepted March 31, 2008 Cyproheptadine displays preclinical activity in myeloma and leukemia Xinliang Mao, Sheng-ben Liang, Rose Hurren, Marcela Gronda, Sue Chow, G Wei Xu, Xiaoming Wang, Reza Beheshti Zavareh, Nazir Jamal, Hans Messner, David W Hedley, Alessandro Datti, Jeff L Wrana, Yuanxiao Zhu, Chang-xin Shi, Kyle Lee, Rodger Tiedemann, Suzanne Trudel, A Keith Stewart, and Aaron D Schimmer* Cancer Genomics and Proteomics, Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Canada The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada The Mayo Clinic, Scottsdale, AZ, United States * Corresponding author; email: aaron.schimmer{at}utoronto.ca. D-cyclins are key regulators of cell division that complex with cyclin dependent kinases to promote Rb phosphorylation and commit cells to a program of DNA replication. D-cyclins are over-expressed in many tumors including multiple myeloma and leukemia and likely contribute to disease progression and chemoresistance. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the off-patent drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G0/G1 phase. Following D-cyclin suppression, cyproheptadine induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of myeloma and leukemia, cyproheptadine inhibited tumor growth without significant toxicity and decreased D-cyclin expression in the tumors. Cyproheptadine-induced apoptosis was preceded by activation of the mitochondrial pathway of caspase activation and was independent of the drug's known activity as an H1 histamine and serotonin receptor antagonist. Thus, cyproheptadine represents a lead for a novel therapeutic agent for the treatment of malignancy. As the drug is well tolerated and already approved in multiple countries for clinical use as an anti-histamine and appetite stimulant, it could be moved directly into clinical trials for cancer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Levine Stem cell transplantation in AIDS-lymphoma Blood, August 13, 2009; 114(7): 1284 - 1285. [Full Text] [PDF]

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