TY - JOUR
T1 - Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds
AU - Li Petri, Giovanna
AU - El Hassouni, Btissame
AU - Sciarrillo, Rocco
AU - Funel, Niccola
AU - Mantini, Giulia
AU - Zeeuw van der Laan, Eveline A.
AU - Cascioferro, Stella
AU - Avan, Amir
AU - Zucali, Paolo Andrea
AU - Zaffaroni, Nadia
AU - Lagerweij, Tonny
AU - Parrino, Barbara
AU - Smid, Kees
AU - Deraco, Marcello
AU - Granchi, Carlotta
AU - Braczko, Alicja
AU - Smolenski, Ryszard T.
AU - Matherly, Larry H.
AU - Jansen, Gerrit
AU - Assaraf, Yehuda G.
AU - Diana, Patrizia
AU - Cloos, Jacqueline
AU - Peters, Godefridus J.
AU - Minutolo, Filippo
AU - Giovannetti, Elisa
PY - 2020/8/18
Y1 - 2020/8/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085931027&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41416-020-0912-9
DO - https://doi.org/10.1038/s41416-020-0912-9
M3 - Article
C2 - 32493992
SN - 0007-0920
VL - 123
SP - 644
EP - 656
JO - British journal of cancer
JF - British journal of cancer
IS - 4
ER -