期刊
BRITISH JOURNAL OF CANCER
卷 123, 期 4, 页码 644-656出版社
SPRINGERNATURE
DOI: 10.1038/s41416-020-0912-9
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资金
- the Law Offices of Peter G. Angelos Grant from the Mesothelioma Applied Research Foundation (MARF), United States
- Fondazione Humanitas, Milano, Italy
- CCA Foundation
- KWF Dutch Cancer Society [10401, 11957]
- Polish National Science Center project [2018/31/B/NZ7/02909]
- University of Pisa
- Italian Association for Cancer Research AIRC/Start-Up grant
- National Institutes of Health [R01 CA53535]
- Eunice and Milton Ring Endowed Chair for Cancer Research [R01 CA53535]
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.
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