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Triapine (3-aninopyridine-2-carboxaldehyde thiosemicarbazone) Induces Apoptosis in Ovarian Cancer Cells

Wei Chen, MD

Alan C. Sartorelli, PhD

Peter Schwartz, MD

Thomas Rutherford, MD, PhD

Departments of Obstetrics and Gynecology and Pharmacology, Yale University School of Medicine, New Haven, Connecticut; Department of Obstetries and Gynecology, Nanfang Hospital, The First Military Medical University, Guangzhou, China

Gil Mor, MD, PhD

Departments of Obstetrics and Gynecology and Pharmacology, Yale University School of Medicine, New Haven, Connecticut; Department of Obstetries and Gynecology, Nanfang Hospital, The First Military Medical University, Guangzhou, China; Department of Obstetrics and Gynecology, Yale University School of Medicine, P.O. Box 208063, 333 Cedar St., FMB 301, New Haven, CT 06520-8063 gil.mor{at}yale.edu

Objectives: Triapine (Vion Pharmaceuticals, New Haven CT) is a potent ribonucleotide reductase inhibitor which exerts its antineoplastic activity by inhibiting DNA synthesis and repair. The objectives of this study were: (1) to determine whether Triapine has cytotoxic effects on epithelial ovarian cancer (EOC) cells; (2) to characterize the apoptotic cascade induced in response to this agent; and (3) to determine its utility in combination treatment with carboplatin and paclitaxel.

Methods: Five EOC cell lines were treated with tenfold dilutions of Triapine (0.1 to 100 µM) for 24 and 48 hours. Cell viability was determined by the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega Corp, Madison, WI) and the morphologic features of apoptosis were observed using Hoechst staining. The apoptotic cascade was characterized by Western blot analyses.

Results: All EOC cell lines treated with Triapine showed decreased cell viability in a time- and dose-dependent manner. Hoechst staining revealed nuclear shrinkage and chromatin condensation and fragmentation, which correlated with occurrence of apoptosis. Western blots demonstrated that Bid activation was one of the initiating signals involved in the cascade. In addition, cleavage of XIAP and down-reglation of Akt were observed. We also demonstrated that Triapine enhances the cytotoxic effects of carboplatin and pacliaxel.

Conclusions: The present findings demonstrate that Triapine induces cell death through the induction of apoptosis. The initial activation of Bid indicates the involvement of the mitochondrial pathway. The demonstration that Triapine is an effective addition to a carboplatin regimen suggests the possibility of a new combination therapy for ovarian cancer.

Key Words: Triapine • apoptosis • caspase • ovarian cancer

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