Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

Shah O.J.; Lin X.; Li L.Huang X.Li J.Anderson M.G.Tang H.Rodriguez L.E.Warder S.E.McLoughlin S.Chen J.Palma J.Glaser K.B.Donawho C.K.Fesik S.W.Shen Y.

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Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

机译：Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

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Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第28期|12634-12639|共6页
作者
Shah O.J.; Lin X.; Li L.Huang X.Li J.Anderson M.G.Tang H.Rodriguez L.E.Warder S.E.McLoughlin S.Chen J.Palma J.Glaser K.B.Donawho C.K.Fesik S.W.Shen Y.;
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作者单位

Oncology Division, Abbott Park, IL 60064-6121, United States;

Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Apoptosis; Aurora kinase; Bcl-XL; Polyploidy;

Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization

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