Cyproheptadine displays preclinical activity in myeloma and leukemia.

Abstract

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent 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.

• Authors: 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
• Journal: Blood (Blood) Vol. 112 Issue 3 Pg. 760-9 (Aug 01 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18502826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND2 protein, human
• CCND3 protein, human
• Ccnd3 protein, mouse
• Cyclin D2
• Cyclin D3
• Cyclins
• Cyclin D1
• Cyproheptadine

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Cyclin D1 (genetics)
• Cyclin D2
• Cyclin D3
• Cyclins (genetics)
• Cyproheptadine (pharmacology, therapeutic use)
• Drug Screening Assays, Antitumor
• Gene Expression Regulation (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Mice
• Multiple Myeloma (drug therapy, pathology)