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

• Published in: Radiation oncology (London, England) England), 2009-10, Vol.4 (1), p.47-47, Article 47
• Main Authors: Zerp, Shuraila F, Stoter, Rianne, Kuipers, Gitta, Yang, Dajun, Lippman, Marc E, van Blitterswijk, Wim J, Bartelink, Harry, Rooswinkel, Rogier, Lafleur, Vincent, Verheij, Marcel
• Format: Article
• Language: English
• Subjects: Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Blotting, Western; Cell Line, Tumor; Combined Modality Therapy; Dose-Response Relationship, Radiation; Gossypol - analogs & derivatives; Gossypol - pharmacology; Health aspects; Humans; JNK Mitogen-Activated Protein Kinases - drug effects; JNK Mitogen-Activated Protein Kinases - radiation effects; Physiological aspects; Protein kinases; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Radiation-Sensitizing Agents - pharmacology; Radiotherapy; Signal Transduction - drug effects; Signal Transduction - radiation effects
• ISSN: 1748-717X; 1748-717X
• DOI: 10.1186/1748-717X-4-47

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. 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-X(L) 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. AT-101 induced apoptosis in a time- and dose-dependent fashion, with ED50 values of 1.9 and 2.4 microM 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. 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.