6533b7d7fe1ef96bd1267ab4

RESEARCH PRODUCT

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds.

Elisa GiovannettiGodefridus J. PetersGodefridus J. PetersAlicja BraczkoGiovanna Li PetriGiovanna Li PetriEveline A.n. Zeeuw Van Der LaanNadia ZaffaroniGiulia MantiniTonny LagerweijPatrizia DianaFilippo MinutoloLarry H. MatherlyGerrit JansenMarcello DeracoRyszard T. SmolenskiBarbara ParrinoNiccola FunelYehuda G. AssarafKees SmidJacqueline CloosAmir AvanAmir AvanRocco SciarrilloStella CascioferroCarlotta GranchiPaolo Andrea ZucaliBtissame El Hassouni

subject

MesotheliomaCancer ResearchPleural NeoplasmsCell Culture TechniquesPemetrexedDeoxycytidineArticle03 medical and health sciencesMice0302 clinical medicinelactate dehydrogenase inhibitorsIn vivoAntigens NeoplasmCell Line TumormedicineGene silencingAnimalsHumansMesotheliomaEnzyme InhibitorsCarbonic Anhydrase IXPeritoneal Neoplasms030304 developmental biology0303 health sciencesL-Lactate DehydrogenaseCell growthChemistryhypoxiaMesothelioma MalignantDrug SynergismHypoxia (medical)Translational researchmedicine.diseaseSettore CHIM/08 - Chimica FarmaceuticaXenograft Model Antitumor AssaysGemcitabineGemcitabineCell HypoxiaGene Expression Regulation NeoplasticPemetrexedOncologyDrug Resistance Neoplasm030220 oncology & carcinogenesisPeritoneal mesotheliomaCancer researchFemalemedicine.symptomProton-Coupled Folate Transportermedicine.drug

description

Abstract Background Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. Methods Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. Results Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. Conclusions This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors.

10.1038/s41416-020-0912-9https://pubmed.ncbi.nlm.nih.gov/32493992