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

Abstract

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.

Cytoprotective and nonprotective autophagy in cancer therapy

“…13 In contrast, in a recent study where hydroxychloroquine was administered at a dose of 162 mg/kg, approximately equivalent to a human dose of 800 mg, tumor growth delay induced by erlotinib is markedly increased in the H358 lung cancer cell line. Interestingly, even at a dose that is relatively high compared with most other published in vivo work, chloroquine demonstrates only minimal extension of tumor growth delay in the H460 tumor cell line 14 despite the fact that chloroquine is equally effective in sensitization of these two cell lines in culture.…”

Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells in vitro

“…Acta Pharmacologica Sinica npg growth factor receptor (EGFR) [22] , and of ABT-737, the Bcl-2 inhibitor [23] . Our results showed that LDM and CQ individually reduced tumor growth in vitro and in vivo.…”

A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

“…17 In contrast to apoptosis, autophagy is generally a cytoprotective mechanism that maintains intracellular homeostasis by removing harmful mal-folded proteins, protein aggregates, and damaged organelles, 18 whereas autophagy inhibition promotes BH3-mimetic lethality. 19 Importantly, a recent study demonstrated that Bim inhibits autophagy by sequestering Beclin-1 at microtubules. 20 Conversely, histone deacetylase inhibitors (HDACIs) upregulate Bim in tumor cells, including MM cells.…”