PMID- 22515519
OWN - NLM
STAT- MEDLINE
DCOM- 20121003
LR  - 20191027
IS  - 1873-5576 (Electronic)
IS  - 1568-0096 (Linking)
VI  - 12
IP  - 6
DP  - 2012 Jul
TI  - Acid ceramidase as a chemotherapeutic target to overcome resistance to the 
      antitumoral effect of choline kinase alpha inhibition.
PG  - 617-24
AB  - We have analyzed the response of primary cultures derived from tumor specimens of 
      non small cell lung cancer (NSCLC) patients to choline kinase alpha (ChoKalpha) 
      inhibitors. ChoKalpha 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 ChoKalpha inhibitors also display increased levels of ASAH1. 
      Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the 
      antiproliferative effect of ChoKalpha inhibitors. Thus, the determination of the 
      levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKalpha specific 
      inhibition and represents a model for combinatorial treatments of ChoKalpha 
      inhibitors and ASAH1 inhibitors. Considering that ChoKalpha 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.
FAU - Ramirez de Molina, A
AU  - Ramirez de Molina A
AD  - Traslational Oncology Unit, Instituto de Investigacion Sanitaria IdiPAZ, Madrid, 
      Spain.
FAU - de la Cueva, A
AU  - de la Cueva A
FAU - Machado-Pinilla, R
AU  - Machado-Pinilla R
FAU - Rodriguez-Fanjul, V
AU  - Rodriguez-Fanjul V
FAU - Gomez del Pulgar, T
AU  - Gomez del Pulgar T
FAU - Cebrian, A
AU  - Cebrian A
FAU - Perona, R
AU  - Perona R
FAU - Lacal, J C
AU  - Lacal JC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Curr Cancer Drug Targets
JT  - Current cancer drug targets
JID - 101094211
RN  - 0 (1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane 
      dibromide)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Butanes)
RN  - 0 (Endocannabinoids)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ethanolamines)
RN  - 0 (Myristates)
RN  - 0 (Oleic Acids)
RN  - 0 (Propanolamines)
RN  - 0 (Pyridinium Compounds)
RN  - 111-58-0 (N-oleoylethanolamine)
RN  - 60847-25-8 (2-(N-myristoylamino)-1-phenyl-1-propanol)
RN  - EC 2.7.1.32 (CHKA protein, human)
RN  - EC 2.7.1.32 (Choline Kinase)
RN  - EC 3.5.1.23 (ASAH1 protein, human)
RN  - EC 3.5.1.23 (Acid Ceramidase)
SB  - IM
MH  - Acid Ceramidase/*antagonists & inhibitors/genetics/metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Biomarkers, Tumor/*metabolism
MH  - Butanes/pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*enzymology/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Choline Kinase/*antagonists & inhibitors/metabolism
MH  - Dose-Response Relationship, Drug
MH  - *Drug Resistance, Neoplasm
MH  - Endocannabinoids
MH  - Enzyme Inhibitors/*pharmacology
MH  - Ethanolamines/pharmacology
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Lung Neoplasms/*enzymology/genetics/pathology
MH  - Molecular Targeted Therapy
MH  - Myristates/pharmacology
MH  - Oleic Acids
MH  - Propanolamines/pharmacology
MH  - Pyridinium Compounds/pharmacology
MH  - Tumor Cells, Cultured
MH  - Up-Regulation
EDAT- 2012/04/21 06:00
MHDA- 2012/10/04 06:00
CRDT- 2012/04/21 06:00
PHST- 2011/11/23 00:00 [received]
PHST- 2012/03/02 00:00 [revised]
PHST- 2012/03/02 00:00 [accepted]
PHST- 2012/04/21 06:00 [entrez]
PHST- 2012/04/21 06:00 [pubmed]
PHST- 2012/10/04 06:00 [medline]
AID - CCDT-EPUB-20120419-002 [pii]
AID - 10.2174/156800912801784811 [doi]
PST - ppublish
SO  - Curr Cancer Drug Targets. 2012 Jul;12(6):617-24. doi: 10.2174/156800912801784811.