Targeted sensitization of tumor cells for radiation through monocarboxylate transporters 1 and 4 inhibition in vitro

Abstract

Objectives

Monocarboxylate transporters (MCT) 1, 2 and 4 play an important role in tumor metabolism. The amount of lactate transported by MCT’s highly correlates with overall survival. Furthermore, glycolysis and hypoxia are possible causes for radiation resistance.

Materials and methods

An oral squamous cell carcinoma cell line (CAL27, ATCC) was analyzed in an in vitro cell assay. After incubation with two different inhibitors for MCT1 (AR-C122982/SR-13800 and AR-C155858/SR-13801, Tocris) or for MCT4 (simvastatin, Sigma-Aldrich and 2-cyano-3-(4-hydroxyphenyl)-2-propenoic acid (CHC), Tocris), cells were irradiated with six gray with a Gammacell 2000 (Nuklear Data). For analysis, cell counting assay, wound healing assay, MTT assay and clonogenic assay were applied.

Results

Cell counting assay showed significant lower results for simvastatin, CHC and for the highest concentrations of AR-C122982 and AR-C155858 (p < 0.03). Additionally, cell counts decreased significantly with irradiation after 72 hours (p < 0.05) only for AR-C122982, CHC and simvastatin. The clonogenic assay confirmed these results with substantially reduced growth when incubated with CHC, simvastatin and AR-C155858 (p < 0.002). Furthermore, MCT1 and 4 inhibition led to highly reduced migration (p < 0.05). There again, comparing the wound healing assay of irradiated to non-irradiated tests showed contrary results (controls: p < 0.001; AR-C155858: p > 0.05; AR-C122982: p > 0.32; CHC: p > 0.1; simvastatin p > 0.1). The MTT assay presented significant effects with MCT1 and 4 inhibition (simvastatin/AR-C122982/CHC: p < 0.007). Irradiated cells showed significantly lower expression after only 48 h compared to non-irradiated cells (simvastatin/AR-C122982/CHC: p < 0.02).

Conclusions

Inhibition of MCT, especially MCT4 may represent a possible tool to overcome radiation resistance in tumor cell lines.

Clinical relevance

MCT Inhibitors may be used as a possible therapeutic approach to sensitize OSCC to radiation.

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Acknowledgments

The authors would like to thank the following persons and institutions for their support: Prof. Dr. Paul Taylor, Jutta Bühler, Ute Zerfaß, and Federico Marini (IMBEI).

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Correspondence to Gregor Brandstetter.

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Brandstetter, G., Blatt, S., Goldschmitt, J. et al. Targeted sensitization of tumor cells for radiation through monocarboxylate transporters 1 and 4 inhibition in vitro. Clin Oral Invest (2020). https://doi.org/10.1007/s00784-020-03364-8

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Keywords

  • Monocarboxylate transporter
  • radiation sensitization
  • MCT inhibition
  • tumor metabolism
  • lactate
  • radiation resistance