AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis

Shuraila F. Zerp, Rianne Stoter, Gitta Kuipers, Dajun Yang, Marc E. Lippman, Wim J. van Blitterswijk, Harry Bartelink, Rogier Rooswinkel, Vincent Lafleur, Marcel Verheij

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48 Scopus citations

Abstract

Background: Gossypol, a naturally occurring polyphenolic compound has been identified as a small molecule inhibitor of anti-apoptotic Bcl-2 family proteins. It induces apoptosis in a wide range of tumor cell lines and enhances chemotherapy- and radiation-induced cytotoxicity both in vitro and in vivo. Bcl-2 and related proteins are important inhibitors of apoptosis and frequently overexpressed in human tumors. Increased levels of these proteins confer radio- and chemoresistance and may be associated with poor prognosis. Consequently, inhibition of the anti-apoptotic functions of Bcl-2 family members represents a promising strategy to overcome resistance to anticancer therapies. Methods: We tested the effect of (-)-gossypol, also denominated as AT-101, radiation and the combination of both on apoptosis induction in human leukemic cells, Jurkat T and U937. Because activation of the SAPK/JNK pathway is important for apoptosis induction by many different stress stimuli, and Bcl-XL is known to inhibit activation of SAPK/JNK, we also investigated the role of this signaling cascade in AT-101-induced apoptosis using a pharmacologic and genetic approach. Results: AT-101 induced apoptosis in a time- and dose-dependent fashion, with ED 50values of 1.9 and 2.4 μM in Jurkat T and U937 cells, respectively. Isobolographic analysis revealed a synergistic interaction between AT-101 and radiation, which also appeared to be sequence-dependent. Like radiation, AT-101 activated SAPK/JNK which was blocked by the kinase inhibitor SP600125. In cells overexpressing a dominant-negative mutant of c-Jun, AT-101-induced apoptosis was significantly reduced. Conclusion: Our data show that AT-101 strongly enhances radiation-induced apoptosis in human leukemic cells and indicate a requirement for the SAPK/JNK pathway in AT-101-induced apoptosis. This type of apoptosis modulation may overcome treatment resistance and lead to the development of new effective combination therapies.

Original languageEnglish (US)
Article number1748
Number of pages1
JournalRadiation Oncology
Volume4
Issue number1
DOIs
StatePublished - Oct 23 2009

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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    Zerp, S. F., Stoter, R., Kuipers, G., Yang, D., Lippman, M. E., van Blitterswijk, W. J., Bartelink, H., Rooswinkel, R., Lafleur, V., & Verheij, M. (2009). AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. Radiation Oncology, 4(1), [1748]. https://doi.org/10.1186/1748-717X-4-47