Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells

Eur Cytokine Netw. 2009 Sep;20(3):121-30. doi: 10.1684/ecn.2009.0159.


In the present study, we aimed to evaluate the possible synergistic, cytotoxic effects of combination treatment of gossypol and zoledronic acid, in human ovarian cancer cell lines, OVCAR-3 and MDAH-2774, and to elucidate the role of this novel combination treatment on angiogenesis-related molecules in ovarian cancer. The XTT cell viability assay was used for showing cytotoxicity. Both DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used for demonstrating apoptosis. To elucidate the angiogenic molecules affected by combination treatment, mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 ProfilerTM PCR Array (SuperArray, Frederick, MD) in ovarian cancer cell lines, OVCAR-3 and MDAH-2774.The combined treatment resulted in significant, synergistic cytotoxicity, and induced apoptosis. This effect was observed to happen in a dose- and time-dependent manner. Moreover, the combination treatment of 10 microM gossypol and 5 microM zoledronic acid resulted in significant down-regulation (>or= thee-fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3 and MDAH-2774 cells as compared to the untreated control. However, this effect was different in the two ovarian cancer cell lines observed. Gossypol, in combination with zoledronic acid, may provide a rational treatment option for ovarian cancer, not only by direct inhibition of cell proliferation, but also inhibition of angiogenesis-related molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects
  • Diphosphonates / pharmacology*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gossypol / pharmacology*
  • Humans
  • Imidazoles / pharmacology*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Zoledronic Acid


  • Angiogenesis Inducing Agents
  • Diphosphonates
  • Imidazoles
  • RNA, Messenger
  • Zoledronic Acid
  • Caspase 3
  • Caspase 7
  • Gossypol