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Research Articles: Therapeutics, Targets, and Development

Therapeutic interactions between stathmin inhibition and chemotherapeutic agents in prostate cancer

Division of Hematology-Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Sucharita J. Mistry, Division of Hematology-Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1079, New York, NY 10029. Phone: 212-241-5281. E-mail: sucharita.mistry{at}mssm.edu or George F. Atweh, Division of Hematology-Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1079, New York, NY 10029. Phone: 212-241-5293. E-mail: george.atweh{at}mssm.edu

Abstract

Limitations of prostate cancer therapy may be overcome by combinations of chemotherapeutic agents with gene therapy directed against specific proteins critical for disease progression. Stathmin is overexpressed in many types of human cancer, including prostate cancer. Stathmin is one of the key regulators of the microtubule network and the mitotic spindle and provides an attractive therapeutic target in cancer therapy. We recently showed that adenovirus-mediated gene transfer of anti-stathmin ribozyme could suppress the malignant phenotype of prostate cancer cells in vitro. In the current studies, we asked whether the therapeutic effects of stathmin inhibition could be further enhanced by exposure to different chemotherapeutic agents. Exposure of uninfected LNCaP human prostate cancer cells or cells infected with a control adenovirus to Taxol, etoposide, 5-fluorouracil (5-FU), or Adriamycin resulted in modest decrease in proliferation and clonogenicity. Interestingly, exposure of cells infected with an anti-stathmin adenovirus to Taxol or etoposide resulted in a complete loss of proliferation and clonogenicity, whereas exposure of the same cells to 5-FU or Adriamycin potentiated the growth-inhibitory effects of the anti-stathmin ribozyme, but the cells continued to proliferate. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling analysis of uninfected cells or cells infected with a control adenovirus showed modest induction of apoptosis in the presence of different drugs. In contrast, cells infected with the anti-stathmin adenovirus showed a marked increase in apoptosis on exposure to Taxol or etoposide and a modest increase on exposure to 5-FU or Adriamycin. Overall, the effects of combinations of anti-stathmin ribozyme with Taxol or etoposide were synergistic, whereas the effects of combinations of anti-stathmin ribozyme with 5-FU or Adriamycin were additive. Moreover, triple combination of anti-stathmin ribozyme with low noninhibitory concentrations of Taxol and etoposide resulted in a profound synergistic inhibition of proliferation, clonogenicity, and marked induction of apoptosis. This synergy might be very relevant for the treatment of prostate cancer because Taxol and etoposide are two of the most effective agents in this disease. Thus, this combination may provide a novel form of prostate cancer therapy that would avoid toxicities associated with the use of multiple chemotherapeutic agents at full therapeutic doses. [Mol Cancer Ther 2006;5(12):3248–57]

Grant support: Department of Defense Research grants W81XWH-04-1-0219 (G.F. Atweh) and W81XWH-04-1-0673 (S.J. Mistry).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/27/06; revised 8/24/06; accepted 10/25/06.

This article has been cited by other articles:

				S. J. Mistry, A. Bank, and G. F. Atweh Synergistic Antiangiogenic Effects of Stathmin Inhibition and Taxol Exposure Mol. Cancer Res., August 1, 2007; 5(8): 773 - 782. [Abstract] [Full Text] [PDF]