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10.1245/s10434-006-9298-z
Annals of Surgical Oncology 14:1763-1771 (2007)
© 2007 Society of Surgical Oncology
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Original Article

TAT-Bim Induces Extensive Apoptosis in Cancer Cells

Hiroyuki Kashiwagi1, Jonathan E. McDunn1,2, Peter S. Goedegebuure1,5, Mary C. Gaffney1, Katherine Chang2, Kathryn Trinkaus3, David Piwnica-Worms4, Richard S. Hotchkiss2 and William G. Hawkins1,5

1 Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
3 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
4 Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
5 Alvin J. Siteman Cancer Center, St. Louis, MO 63110, USA

Correspondence: Address correspondence and reprint requests to: William G. Hawkins, Department of Surgery, WUMS, 660 S. Euclid Avenue, Campus Box 8109, St. Louis, MO 63110, USA; E-mail: hawkinsw{at}wustl.edu

Background: Suppression of apoptosis is central to the development of cancer and is associated with resistance to modern adjuvant treatments. Therefore, molecules and pathways of apoptotic processes are critical targets for the development of anti-cancer therapeutics. Since apoptosis is executed by intracellular proteins, molecular approaches must incorporate a method to deliver the treatment into the tumor cells.

Methods: We utilized a peptide that contains two domains, a peptide transduction domain derived from the HIV-1 TAT protein and a biological effector domain, the BH3 domain from the pro-apoptotic Bcl-2 family member Bim. We examined whether this construct (TAT-Bim) induced apoptosis in several cancer cell lines (T-cell lymphoma (EL4), pancreatic cancer (Panc-02), and melanoma (B16)) and whether TAT-Bim treatment synergized with radiation. A mutant TAT-Bim peptide with no biologic activity (TAT-Bim-inactive) was used as a control. C57/BL6 mice were challenged with syngeneic cancer cell lines and the effects of intratumoral TAT-Bim injection on tumor growth and host survival were determined.

Results: TAT-Bim was internalized by all cancer cells within two hours. TAT-Bim resulted in apoptosis in a dose dependent fashion in all cell lines and sublethal irradiation augmented the effects of TAT-Bim induced apoptosis. TAT-Bim significantly slowed tumor growth in murine models of pancreatic cancer and melanoma.

Conclusion: TAT-Bim exemplifies a strategy for cancer therapy that involves inducing apoptosis by antagonizing the endogenous anti-apoptotic machinery. Small peptide therapeutics, in combination with traditional adjuvant therapies such as radiation, may provide a valuable ‘second hit’ and drive tumor cells into programmed cell death.

Key Words: Apoptosis • Tat-fusion protein • Bim • Peptide therapeutic






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