Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds
Open Access
- 18 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (4), 644-656
- https://doi.org/10.1038/s41416-020-0912-9
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.Funding Information
- Associazione Italiana per la Ricerca sul Cancro (Start-Up)
- KWF Kankerbestrijding (11957)
This publication has 59 references indexed in Scilit:
- Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporterCancer Chemotherapy and Pharmacology, 2013
- Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatinBritish Journal of Cancer, 2011
- The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistanceCell Death & Disease, 2011
- Onconase mediated NFKβ downregulation in malignant pleural mesotheliomaOncogene, 2011
- The Obligatory Intestinal Folate Transporter PCFT (SLC46A1) Is Regulated by Nuclear Respiratory Factor 1Online Journal of Public Health Informatics, 2010
- PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cellsBiochemical and Biophysical Research Communications, 2008
- The Proton-Coupled Folate Transporter: Impact on Pemetrexed Transport and on Antifolates Activities Compared with the Reduced Folate CarrierMolecular Pharmacology, 2008
- The molecular identity and characterization of a Proton-Coupled Folate Transporter—PCFT; biological ramifications and impact on the activity of pemetrexed—12 06 06Cancer and Metastasis Reviews, 2007
- TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesisProceedings of the National Academy of Sciences of the United States of America, 2006
- Postconfluent multilayered cell line cultures for selective screening of gemcitabineEuropean Journal of Cancer, 1998