Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells

Abstract

As a consequence of altered glucose metabolism, cancer cell intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs). MCT 1 and MCT4 are frequently overexpressed in tumors, and recently, MCT inhibition has been reported to exert antineoplastic effects. In the present study, MCT1 and MCT4 levels were assessed in esophageal adenocarcinoma (EAC) cells and the effects of the MCT-1 selective inhibitor AZD3965, hypoxia, and a glucose overload were evaluated in vitro. Two EAC cell lines (OE33 and OACM5.1C) were treated with AZD3965 (10–100 nM) under different conditions (normoxia/hypoxia) and also different glucose concentrations, and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi), and lactate levels were evaluated. MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small proportion of OACM5.1C cells. Glucose addition did not have any effect on apoptosis nor cell proliferation. AZD3965 increased apoptosis and reduced proliferation of OACM5.1C cells, effects which were abrogated when cells were growing in hypoxia. MCT1 inhibition increased intracellular lactate levels in all the cells evaluated, but this increase was higher in cells expressing only MCT1 and did not affect oxidative stress. AZD3965 induced a decrease in pHi of cells displaying low levels of MCT4 and also increased the sodium/hydrogen exchanger 1 (NHE-1) expression on these cells. These data provide in vitro evidence supporting the potential of MCT inhibitors as novel antineoplastic drugs for EAC and highlight the importance of achieving a complete MCT inhibition.

Effects of Lactate Transport Inhibition by AZD3965 in Muscle-Invasive Urothelial Bladder Cancer

“…A decrease in the expression of caspase 3 in AZD3965-treated 253J cells corroborates that these cells overcome the treatment effect, sustaining cell viability, which is also confirmed by the lack of changes in the expression profile of PARP and BCL-XL. Similar effects regarding apoptosis signaling under low MCT4 expression have already been observed [33,41], although other studies report that cell death with this compound may be undertaken through different routes (as autophagy or even necrosis) [27,39]. Once a single dose of AZD3965 did not result in a pronounced effect on cell viability (reductions of about 20-30% when comparing to control condition), we attempted a different modality, according to the study by Benyahia et al [29], in which cells were exposed to daily doses of the compound for 72 h. This approach had a strong cytotoxic effect, especially in HT1376R cells, when higher doses of the compound were used (1000 and 10,000 nM).…”

Exploring monocarboxylate transporter inhibition for cancer treatment

“…For example, if cell acidifiers were co-administered with AZD3965 it is highly possible that better results may be obtained. AZD3965 decreases intracellular pH by causing lactate accumulation but activates the NHE1 which then tries to compensate for the lower pH [ 206 ]. Inhibiting NHE1 should therefore increase AZD3965 efficiency.…”

“…Acriflavine treatment significantly inhibited grown and self-renewal of glioblastoma neurosphere lines in vitro, and treatment in mouse xenografts inhibited tumor progression [204]. Acriflavine is a topical antibacterial agent that has been found to be a potent inhibitor of hypoxia-inducible factor-1 (HIF-1) [205].…”

The relationship and clinical significance of lactylation modification in digestive system tumors

“…Silencing the Caprin-1 gene can inhibit EC cell proliferation and glycolysis, as well as reduce the expression of METTL3 and the tumor-related protein WTAP, thereby, affecting tumor growth [ 86 ]. Similarly, inhibiting lactate transport also demonstrates anti-tumor effects, as blocking monocarboxylate transporter increases the apoptotic levels of EC cells and reduces their proliferative capacity [ 87 ]. Thus, targeted regulation of lactate metabolism or protein lactylation processes may become a new strategy for the treatment of EC.…”