title: Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition.
abstract: We have analyzed the response of primary cultures derived from tumor specimens of non small cell lung cancer (NSCLC) patients to choline kinase α (ChoKα) inhibitors. ChoKα inhibitors have been demonstrated to increase ceramides levels specifically in tumor cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumors. NSCLC cells with acquired resistance to ChoKα inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKα inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKα specific inhibition and represents a model for combinatorial treatments of ChoKα inhibitors and ASAH1 inhibitors. Considering that ChoKα inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development.
authors.affiliation: Traslational Oncology Unit, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ramírez de Molina
authors.forename: A
authors.initials: A
authors.lastname: de la Cueva
authors.forename: R
authors.initials: R
authors.lastname: Machado-Pinilla
authors.forename: V
authors.initials: V
authors.lastname: Rodriguez-Fanjul
authors.forename: T
authors.initials: T
authors.lastname: Gomez del Pulgar
authors.forename: A
authors.initials: A
authors.lastname: Cebrian
authors.forename: R
authors.initials: R
authors.lastname: Perona
authors.forename: J C
authors.initials: JC
authors.lastname: Lacal
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002073:Butanes / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009226:Myristates / Q000494:pharmacology; D009829:Oleic Acids; D011412:Propanolamines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002073:Butanes; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009226:Myristates; D009829:Oleic Acids; D011412:Propanolamines; D011726:Pyridinium Compounds; C033595:N-oleoylethanolamine; C099657:2-(N-myristoylamino)-1-phenyl-1-propanol; C517212:CHKA protein, human; D002797:Choline Kinase; C526693:ASAH1 protein, human; D055573:Acid Ceramidase