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Cell-type-specific sensitivity of bortezomib in the methotrexate-resistant primary central nervous system lymphoma cells

  • Azusa Hayano
  • Yasuo Takashima
  • Ryuya YamanakaEmail author
Original Article

Abstract

Background

Methotrexate (MTX) is used in first-line treatment of primary central nervous system lymphoma (PCNSL), but most cases result in relapse-acquired resistance to MTX. However, only few studies have reported on internal changes and chemotherapies in PCNSL.

Methods

In this study, we generated two MTX-resistant PCNSL cell lines, designated MTX-HKBML and MTX-TK, in addition to a MTX-resistant Burkitt lymphoma cell line, designated MTX-RAJI. We examined gene expression changes and drug sensitivity to a proteasome inhibitor, bortezomib, in these cells.

Results

Cytotoxic tests revealed that the 50% inhibitory concentration for MTX in MTX-HKBML is markedly higher than that in the other two cell lines. Expression of the genes in MTX and folate metabolisms, including gamma-glutamyl hydrolase and dihydrofolate reductase, are upregulated in both MTX-HKBML and MTX-TK, whereas the gene expression of folylpolyglutamate synthetase, thymidylate synthase, and methylenetetrahydrofolate dehydrogenase 1 were upregulated and downregulated in MTX-HKBML and MTX-TK, respectively, on the other hand, bortezomib sensitivity was observed in MTX-TK, as compared with control TK, but not in MTX-HKBML.

Conclusion

These results indicate the cell-type-specific changes downstream of metabolic pathways for MTX and folate, bortezomib sensitivity, and purine and pyrimidine syntheses, in each PCNSL cell line. The MTX-resistant lymphoma cell lines established may be useful for in vitro relapse models for MTX and development of salvage chemotherapy and drug discovery.

Keywords

Primary central nervous system lymphoma Methotrexate Bortezomib Folate metabolism Purine and pyrimidine syntheses 

Notes

Acknowledgements

The study was supported by the MEXT KAKENHI Grant numbers 16H05441, 16K10766, and 18K09001.

Author contributions

AH and RY designed the experiments. AH and YT performed the experiments. AH, YT, and RY analyzed data. AH, YT, and RY wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of financial and non-financial interest exists.

Supplementary material

10147_2019_1451_MOESM1_ESM.pdf (311 kb)
Supplementary file1 (PDF 312 kb)

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Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular Target Therapy for Cancer, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan

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