Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer

Molecular Cancer

Research

Sara Murphy¹  Luigi Marchionni¹  Charles M Rudin¹  Rebekah L Zinn¹  Irina Dobromilskaya¹  Eric E Gardner¹  Christine L Hann¹ 

[1] Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Cancer Research Building 2, Room 544 1550 Orleans Street, Baltimore, MD, USA;

关键词: Autophagy;    Apoptosis;    ABT-737;    Chloroquine;    Primary xenograft;   

DOI  :  10.1186/1476-4598-12-16

 received in 2012-08-27, accepted in 2013-02-27,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundNew therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies.MethodsWe explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models.ResultsCombination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT-737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models.ConclusionThese data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC.

【 授权许可】

Unknown   
© Zinn et al; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.