5-Oxoproline Enhances 4-Hydroxytamoxifen-induced Cytotoxicity by Increasing Oxidative Stress in MCF-7 Breast Cancer Cells

Background/aim: Monocarboxylate transporters (MCTs) transport short-chain monocarboxylates, such as lactate, and have been reported to be related to poor prognosis in breast cancer. Our previous studies showed that a high glucose state altered MCT expression and changed the sensitivity of the tamoxifen active metabolite 4-hydroxytamoxifen (4-OHT) via hypoxia-inducible factor-1α (HIF-1α) protein expression. We hypothesized that MCT inhibitors affect 4-OHT-induced cytotoxicity under normal glucose conditions by decreasing HIF-1α protein expression. To test this hypothesis, we evaluated the combined effect of MCT inhibitor and 4-OHT using the estrogen receptor (ER)-positive breast cancer cell line MCF-7, under normal glucose conditions.

Materials and methods: Expression of MCTs and oxidative stress markers was evaluated by real-time PCR. Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Reactive oxygen species (ROS) were measured using the cell permeability probe 2',7'-dichlorodihydrofluorescein diacetate.

Results: MCT1 expression increased under normal glucose conditions. The MCT1 substrate/inhibitor, 5-oxoproline (5-OP), enhanced 4-OHT-induced cytotoxicity. Bindarit, a selective MCT4 inhibitor, decreased 4-OHT sensitivity, similar to results of our previous study under high glucose conditions. In contrast, the combination of 5-OP and 4-OHT decreased ATP levels compared with that by 4-OHT alone in MCF-7 cells. Furthermore, 5-OP significantly increased the ROS production induced by 4-OHT.

Conclusion: 5-OP enhances 4-OHT-induced cytotoxicity in ER-positive breast cancer cells under normal glucose conditions.

Comments：

The study aimed to investigate the effect of monocarboxylate transporter (MCT) inhibitors on the cytotoxicity of the tamoxifen active metabolite 4-hydroxytamoxifen (4-OHT) in the estrogen receptor (ER)-positive breast cancer cell line MCF-7 under normal glucose conditions. The authors hypothesized that MCT inhibitors would decrease HIF-1α protein expression and affect 4-OHT-induced cytotoxicity. The study found that MCT1 expression increased under normal glucose conditions, and the MCT1 substrate/inhibitor, 5-oxoproline (5-OP), enhanced 4-OHT-induced cytotoxicity. In contrast, the selective MCT4 inhibitor Bindarit decreased 4-OHT sensitivity, similar to the results of a previous study under high glucose conditions. The combination of 5-OP and 4-OHT decreased ATP levels compared to 4-OHT alone in MCF-7 cells, and 5-OP significantly increased ROS production induced by 4-OHT. The authors concluded that 5-OP enhances 4-OHT-induced cytotoxicity in ER-positive breast cancer cells under normal glucose conditions.

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