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, Aaron D. Schimmer

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

D-cyclins are regulators of cell division that act in a complex with cyclindependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G 0/G 1 phase. After 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. 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. Because the drug is well tolerated and already approved in multiple countries for clinical use as an antihistamine and appetite stimulant, it could be moved directly into clinical trials for cancer.

Original languageEnglish (US)
Pages (from-to)760-769
Number of pages10
JournalBlood
Volume112
Issue number3
DOIs
StatePublished - Aug 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Mao, X., Liang, S. B., Hurren, R., Gronda, M., Chow, S., Wei Xu, G., Wang, X., Zavareh, R. B., Jamal, N., Messner, H., Hedley, D. W., Datti, A., Wrana, J. L., Zhu, Y., Shi, C. X., Lee, K., Tiedemann, R., Trudel, S., Keith Stewart, A., & Schimmer, A. D. (2008). Cyproheptadine displays preclinical activity in myeloma and leukemia. Blood, 112(3), 760-769. https://doi.org/10.1182/blood-2008-02-142687