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Radiation Oncology
Published in: Radiation Oncology 1/2009

Open Access 01-12-2009 | Research

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

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

Published in: Radiation Oncology | Issue 1/2009

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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 ED50 values 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.
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Metadata
Title
AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis
Authors
Shuraila F Zerp
Rianne Stoter
Gitta Kuipers
Dajun Yang
Marc E Lippman
Wim J van Blitterswijk
Harry Bartelink
Rogier Rooswinkel
Vincent Lafleur
Marcel Verheij
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2009
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/1748-717X-4-47

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