title: Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death.
abstract: Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Salas
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Marsh
authors.affiliation: Departments of Anatomic Pathology and Molecular Genetics, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rubin
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Debnath
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000962:Antimalarials; C117307:KRAS protein, human; D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D016283:Proto-Oncogene Proteins p21(ras)