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

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The Journal of the Society for Gynecologic Investigation: JSGI Aims and scope Submit manuscript

Abstract

Objectives

Triapine (Vion Pharmaceuticals, New Haven, CT) is a potent ribonucleotide reductase inhibitor which exerts its antineoplastic acitivity 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 the 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-regulation of Akt were observed. We also demonstrated that Triapine enhances the cytotoxic effects of carboplatin and paclitaxel.

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. (J Soc Gynecol Investig 2006;13:145-52) Copyright © 2006 by the Society for Gynecologic Investigation.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Yale University School of Medicine, P.O. Box 208063, 333 Cedar St., FMB 301, New Haven, Connecticut, 06520-8063, USA

    Ayesha B. Alvero MD, Wei Chen MD, Alan C. Sartorelli PhD, Peter Schwartz MD, Thomas Rutherford MD, PhD & Gil Mor MD, PhD

  2. Department of Obstetrics and Gynecology, Nanfang Hospital, The First Military Medical University, Guangzhou, China

    Ayesha B. Alvero MD, Wei Chen MD, Alan C. Sartorelli PhD, Peter Schwartz MD, Thomas Rutherford MD, PhD & Gil Mor MD, PhD

Authors
  1. Ayesha B. Alvero MD
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  2. Wei Chen MD
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  3. Alan C. Sartorelli PhD
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  4. Peter Schwartz MD
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  5. Thomas Rutherford MD, PhD
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  6. Gil Mor MD, PhD
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Corresponding author

Correspondence to Gil Mor MD, PhD.

Additional information

Supported by the Discovery to Cure Research Fund and Nicolas Brady.

The authors wish to thank Dr Anna Rice for help in the analysis of the combination treatments.

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Alvero, A.B., Chen, W., Sartorelli, A.C. et al. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) Induces Apoptosis in Ovarian Cancer Cells. Reprod. Sci. 13, 145–152 (2006). https://doi.org/10.1016/j.jsgi.2005.11.004

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  • DOI: https://doi.org/10.1016/j.jsgi.2005.11.004

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