Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells
Background
As a consequence of altered glucose metabolism, cancer cells intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs).
MCTs are frequently overexpressed in tumors, MCT1 in the well oxygenated areas and MCT4 in hypoxic regions, and recent evidence has reported that MCT inhibition can exert antineoplastic effects, but this aspect has not been investigated in esophageal adenocarcinoma (EAC) yet. In the present study, MCT1 and MCT4 levels were assessed in EAC cells and the effects of MCT-1 selective inhibitor AZD3965, hypoxia and a glucose overload were evaluated in vitro .
Methods
Two EAC cell lines (OE33 and OACM5.1C) were treated with different concentrations of AZD3965 (10-100nM) in the presence or absence of a glucose overload under normoxic or hypoxic conditions and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi) and lactate levels were evaluated.
Results
MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small population of the metastatic 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 NHE-1 expression on these cells.
Conclusion
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Posted 28 Sep, 2020
Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells
Posted 28 Sep, 2020
Background
As a consequence of altered glucose metabolism, cancer cells intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs).
MCTs are frequently overexpressed in tumors, MCT1 in the well oxygenated areas and MCT4 in hypoxic regions, and recent evidence has reported that MCT inhibition can exert antineoplastic effects, but this aspect has not been investigated in esophageal adenocarcinoma (EAC) yet. In the present study, MCT1 and MCT4 levels were assessed in EAC cells and the effects of MCT-1 selective inhibitor AZD3965, hypoxia and a glucose overload were evaluated in vitro .
Methods
Two EAC cell lines (OE33 and OACM5.1C) were treated with different concentrations of AZD3965 (10-100nM) in the presence or absence of a glucose overload under normoxic or hypoxic conditions and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi) and lactate levels were evaluated.
Results
MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small population of the metastatic 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 NHE-1 expression on these cells.
Conclusion
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8