Drug research: Cyproheptadine
Xinliang Mao1, Sheng-ben Liang1, Rose Hurren1, Marcela Gronda1, Sue Chow1, G. Wei Xu1, Xiaoming Wang1, Reza Beheshti Zavareh1, Nazir Jamal1, Hans Messner1, David W. Hedley1, Alessandro Datti2, Jeff L. Wrana2, Yuanxiao Zhu3, Chang-xin Shi3, Kyle Lee1, Rodger Tiedemann3, Suzanne Trudel1, A. Keith Stewart3, and Aaron D. Schimmer1
1 Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON; 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; and 3 Mayo Clinic, Scottsdale, AZ
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 G0/G1 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.
1 Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON; 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; and 3 Mayo Clinic, Scottsdale, AZ
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 G0/G1 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.
posted by gwg at 9:13 PM
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