期刊
BRITISH JOURNAL OF CANCER
卷 110, 期 1, 页码 172-182出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.681
关键词
pancreatic ductal adenocarcinoma; hypoxia; lactate dehydrogenase inhibitors; gemcitabine
类别
资金
- EORTC-PAMM
- CCA-VICI foundation [2012-5-07]
- Netherlands Organization for Scientific Research (NWO, Veni grant)
- AIRC-Marie Curie (International Fellowship)
- Istituto Toscano Tumori grant
- European Union [FP7-REGPOT-2012-CT2012-31637-IMBRAIN, GA-2011-299026]
Background: Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. Methods: Lactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. Results: Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O-2), where the novel LDH-A inhibitors proved to be particularly effective (e. g., with IC50 values of 0.9 vs 16.3 mu M for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. Conclusion: Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.
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