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A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells, and modulated the expression of the human equilibrative transporter-1.

Authors :
Giovannetti E
Leon LG
Gómez VE
Zucali PA
Minutolo F
Peters GJ
Source :
Nucleosides, nucleotides & nucleic acids [Nucleosides Nucleotides Nucleic Acids] 2016 Dec; Vol. 35 (10-12), pp. 643-651.
Publication Year :
2016

Abstract

Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O <subscript>2</subscript> tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC <subscript>50</subscript> s. However, the simultaneous addition of NHI-1 was synergistic (combination index < 1). Flow cytometry demonstrated that hypoxia caused a G1 arrest, whereas the combination of NHI-1 significantly increased gemcitabine-induced cell death. Finally, the mRNA expression levels of the human equilibrative transporter-1 (hENT1) were significantly down-regulated under hypoxia, but treatment with NHI-1 was associated with a recovery of hENT1 expression. In conclusion, our data show that hypoxia increased MPM resistance to gemcitabine. However, cell death induction and modulation of the key transporter in gemcitabine uptake may contribute to the synergistic interaction of gemcitabine with the LDH-A inhibitor NHI-1 and support further studies for the rational development of this combination.

Details

Language :
English
ISSN :
1532-2335
Volume :
35
Issue :
10-12
Database :
MEDLINE
Journal :
Nucleosides, nucleotides & nucleic acids
Publication Type :
Academic Journal
Accession number :
27906635
Full Text :
https://doi.org/10.1080/15257770.2016.1149193