Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Oncogene ; 39(13): 2756-2771, 2020 03.
Article in English | MEDLINE | ID: mdl-32015486

ABSTRACT

Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.


Subject(s)
Aldehyde Dehydrogenase 1 Family/antagonists & inhibitors , Aldehyde Dehydrogenase/antagonists & inhibitors , Aldehyde Oxidoreductases/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Retinal Dehydrogenase/antagonists & inhibitors , Aged , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase/metabolism , Aldehyde Dehydrogenase 1 Family/genetics , Aldehyde Dehydrogenase 1 Family/metabolism , Aldehyde Oxidoreductases/genetics , Aldehyde Oxidoreductases/metabolism , Alkynes/pharmacology , Alkynes/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cisplatin/pharmacology , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Gene Amplification , Glutathione/metabolism , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Mice , Middle Aged , Reactive Oxygen Species/metabolism , Retinal Dehydrogenase/genetics , Retinal Dehydrogenase/metabolism , Sulfhydryl Compounds/pharmacology , Sulfhydryl Compounds/therapeutic use , Up-Regulation , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...