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

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.

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…Second, LDHA is involved in cancer invasion and CSC phenotype through the acidic microenvironment maintained by lactate output (130). When LDHA is highly expressed, mesothelioma becomes more aggressive (131). LDHA is significantly related to octamer-binding transcription factor 4, which plays a key role in the self-renewal of embryonic stem cells in gastric cancer (132).…”

Hypoxia as a driver of resistance to immunotherapy

“…Hypoxic areas are heterogeneously distributed within the tumor bulk, because the continuous alternation between vessel formation and collapse determines conditions of cycling hypoxia 3 and re-oxygenation (Vaupel et al, 2004). While the physiological pressure of O 2 (pO 2 ) in normal tissues is between 1 and 11%, the mean tumor pO 2 is below 2% (Li Petri et al, 2020;Mckeown, 2014;Muz & Azab, 2015;Raz et al, 2014). Depending on pO 2 , hypoxic oscillations, concomitant shortage of other nutrients such as glucose and amino acids, cancer cells growing in hypoxic areas can either slow their proliferation rate, hence undergoing necro-apoptosis, or adapt to the hypoxic conditions.…”

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

“…Complex I Metformin, rotenone, phenformin [31] Complex IV Arsenic trioxide [32] OXPHOS Complex V Oligomycin [78] Hexokinase 2-deoxy-D-glucose [79] Pyruvate Dehydrogenase CPI-613 (devimistat) [32] Glycolysis LDH-A N-hydroxyindole-based inhibitors [80,81] rate is strictly dependent on several factors, including genetic signatures and performance status scale [75,76] . Recognizing AdipoRon as a potential candidate in gemcitabine-based therapy may provide additional hopes for advanced PDAC patients.…”

“…Since an OXPHOS impairment has also been observed in response to AdipoRon administration [68,69] , it is plausible to imagine a link between the damage that occurred at this organelle and the ability to sensitize PDAC resistant cells to gemcitabine. While the aberrant glycolysis usage is considered a metabolic feature of drug resistance in tumor cells [30,79] , after AdipoRon stimulation, this compensatory mechanism could be exploited to completely eradicate the minimal residual disease [Table 1] [69,80,81] . Besides the metabolic outlook, another potential mechanistic way to corroborate the AdipoRon-mediated gemcitabine sensitization could be represented by the ABC transporters, which have recently been implicated in chemotherapy resistance, expressly in PDAC [21][22][23] .…”