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Published on: September 18, 2013

Cyproheptadine displays preclinical activity in myeloma and leukemia

Xinliang Mao1, Sheng-ben Liang, Rose Hurren

  • 1Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada.

Blood
|May 27, 2008
PubMed

Insights

The drug cyproheptadine inhibits D-cyclins, crucial for cell division, in leukemia and myeloma cells. This leads to cancer cell death and reduced tumor growth, offering a potential new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • D-cyclins regulate cell division and are overexpressed in hematologic malignancies, contributing to disease progression and chemoresistance.
  • Understanding D-cyclin regulation is vital for developing targeted therapies for cancers like multiple myeloma and leukemia.

Purpose of the Study:

  • To identify inhibitors of the cyclin D2 promoter using a high-throughput screen.
  • To investigate the therapeutic potential of identified compounds in hematologic malignancies.

Main Methods:

  • Conducted a high-throughput screen to identify inhibitors of the cyclin D2 promoter.
  • Tested the effects of the identified drug, cyproheptadine, on myeloma and leukemia cell lines and primary patient samples.
  • Evaluated cyproheptadine's efficacy and toxicity in mouse models of myeloma and leukemia.
  • Investigated the mechanism of cyproheptadine-induced apoptosis.

Main Results:

  • Cyproheptadine was identified as an inhibitor of the cyclin D2 promoter.
  • Cyproheptadine decreased D-cyclin expression (D1, D2, D3) and induced G(0)/G(1) cell cycle arrest in cancer cells.
  • Cyproheptadine induced apoptosis in myeloma and leukemia cells preferentially over normal hematopoietic cells.
  • Cyproheptadine inhibited tumor growth in mouse models with minimal toxicity.
  • Apoptosis was mediated by the mitochondrial pathway of caspase activation, independent of histamine/serotonin receptor antagonism.

Conclusions:

  • Cyproheptadine demonstrates significant anti-cancer activity against hematologic malignancies by targeting D-cyclins.
  • The drug exhibits preferential toxicity towards cancer cells and is well-tolerated in preclinical models.
  • Cyproheptadine's established safety profile and existing clinical approval suggest potential for rapid translation into cancer clinical trials.

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