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

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.

• Authors: Azusa Hayano, Yasuo Takashima, Ryuya Yamanaka
• Journal: International journal of clinical oncology (Int J Clin Oncol) Vol. 24 Issue 9 Pg. 1020-1029 (Sep 2019) ISSN: 1437-7772 [Electronic] Japan
• PMID: 30993483 (Publication Type: Journal Article)

Chemical References

• Minor Histocompatibility Antigens
• Bortezomib
• Folic Acid
• MTHFD1 protein, human
• Methylenetetrahydrofolate Dehydrogenase (NADP)
• Thymidylate Synthase
• Peptide Synthases
• folylpolyglutamate synthetase
• Methotrexate

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Bortezomib (administration & dosage, pharmacology)
• Cell Line, Tumor
• Central Nervous System Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (drug effects)
• Folic Acid (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lymphoma (drug therapy, genetics, pathology)
• Lymphoma, Non-Hodgkin (drug therapy, pathology)
• Methotrexate (administration & dosage, pharmacology)
• Methylenetetrahydrofolate Dehydrogenase (NADP) (genetics)
• Minor Histocompatibility Antigens (genetics)
• Molecular Targeted Therapy
• Peptide Synthases (genetics)
• Thymidylate Synthase (genetics)