Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells

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. (AU)

Feasibility of Telemedicine in the Management Strategy of Patients With Lymphoma Amid the COVID-19 Pandemic in Spain: Prospective Observational Study.

BACKGROUND: On March 14, 2020, a state of alarm was declared in Spain due to the spread of SARS-CoV-2. Beyond this date, COVID-19 in the country changed the practice of oncologic care. OBJECTIVE: Since recurrent hospital visits were a potential risk factor for contagion, the aim of this prospective observational study was to analyze the consequences of the COVID-19 pandemic in the health care of patients with lymphoma. METHODS: All data were obtained from the electronic medical record. Variables such as age, sex, reason of the visit, use of the patient portal, changes in management, enrollment in clinical trials, and COVID-19 infection were recorded. RESULTS: In all, 290 patients visited the lymphoma clinic, totaling 437 appointments. The median age was 66 (range 18-94) years, and 157 (54.1%) patients were male. Of them, 214 (73.8%) patients had only 1 visit to the clinic. Only 23 (7.9%) patients did not have access to the patient portal. Amid the COVID-19 pandemic, 78 (26.9%) patients remained in active treatment, 35 (12.1%) experienced delays in their treatments, and 6 (2.1%) experienced treatment discontinuation. During the follow-up, only 7 (2.4%) patients had a COVID-19 infection (6 cases with confirmed polymerase chain reaction test and 1 case with clinical suspicion). Despite the implementation of telemedicine strategies to avoid visits to the hospital, 66 (22.8%) patients had in-person visits at the lymphoma clinic. Patients who attended in-person consultations were younger than those who preferred telemedicine consultations (62 vs 66 years; P=.10) and had less use of the patient portal (17/224, 7.6% vs 6/66, 9%; P=.10), although these differences did not reach statistical significance. Patients who attended in-person visits were more likely to have had only 1 visit to the hospital (29/66, 43.9% vs 185/224, 82.6%; P<.001). Regarding the reason of in-person consultations, more patients were on active treatment in comparison to those using telemedicine resources (37/66, 56.1% vs 42/224, 18.3%; P<.001). Patients with a preference for telemedicine strategies had more surveillance visits (147/224, 65.6% vs 24/66, 36.4%; P<.001). Regarding treatment modifications, more treatment delays (29/224, 12.9% vs 6/66, 9.1%; P=.10) and more definite treatment discontinuations (6/224, 2.7% vs 0/66, 0%; P=.10) were seen in patients using telemedicine resources when compared to patients attending in-person visits, although these differences did not reach statistical significance. Regarding the type of therapy, patients attending in-person visits were more likely to receive an intravenous treatment rather than those using telemedicine (23/66, 62.2% vs 17/224, 40.5%; P<.001). CONCLUSIONS: Telemedicine such as patient portals are feasible strategies in the management of patients with lymphoma during the COVID-19 pandemic, with a reduction of in-person visits to the hospital and a very low contagion rate.

Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells.

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.