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

Giovanna Li Petri, Btissame El Hassouni, Rocco Sciarrillo, Niccola Funel, Giulia Mantini, Eveline A. Zeeuw van der Laan, Stella Cascioferro, Amir Avan, Paolo Andrea Zucali, Nadia Zaffaroni, Tonny Lagerweij, Barbara Parrino, Kees Smid, Marcello Deraco, Carlotta Granchi, Alicja Braczko, Ryszard T. Smolenski, Larry H. Matherly, Gerrit Jansen, Yehuda G. AssarafPatrizia Diana, Jacqueline Cloos, Godefridus J. Peters, Filippo Minutolo, Elisa Giovannetti*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
JournalBritish Journal of Cancer
DOIs
Publication statusAccepted/In press - 1 Jan 2020

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