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

Elisa Giovannetti, Leticia G. Leon, Valentina E. Gómez, Paolo Andrea Zucali, Filippo Minutolo, Godefridus J. Peters

Research output: Contribution to journalArticlepeer-review

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 (O2 tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC50s. 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.

Original languageEnglish
Pages (from-to)643-651
Number of pages9
JournalNucleosides, Nucleotides and Nucleic Acids
Volume35
Issue number10-12
DOIs
Publication statusPublished - Dec 1 2016

Keywords

  • Anticancer nucleosides
  • gemcitabine
  • human equilibrative transporter-1
  • LDH
  • mechanisms of action studies
  • mesothelioma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this