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Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition.
- Source :
-
Current cancer drug targets [Curr Cancer Drug Targets] 2012 Jul; Vol. 12 (6), pp. 617-24. - Publication Year :
- 2012
-
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.
- Subjects :
- Acid Ceramidase genetics
Acid Ceramidase metabolism
Apoptosis drug effects
Butanes pharmacology
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Choline Kinase metabolism
Dose-Response Relationship, Drug
Endocannabinoids
Ethanolamines pharmacology
Humans
Inhibitory Concentration 50
Lung Neoplasms genetics
Lung Neoplasms pathology
Molecular Targeted Therapy
Myristates pharmacology
Oleic Acids
Propanolamines pharmacology
Pyridinium Compounds pharmacology
Tumor Cells, Cultured
Up-Regulation
Acid Ceramidase antagonists & inhibitors
Antineoplastic Agents pharmacology
Biomarkers, Tumor metabolism
Carcinoma, Non-Small-Cell Lung enzymology
Choline Kinase antagonists & inhibitors
Drug Resistance, Neoplasm
Enzyme Inhibitors pharmacology
Lung Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5576
- Volume :
- 12
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Current cancer drug targets
- Publication Type :
- Academic Journal
- Accession number :
- 22515519
- Full Text :
- https://doi.org/10.2174/156800912801784811