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

Hayano, Azusa; Takashima, Yasuo

doi:10.1007/s10147-019-01451-9

Cited by 7 publications

(16 citation statements)

References 41 publications

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“…Nucleotide metabolism is closely associated with tumor initiation and progression, as well as the response to chemotherapy. In terms of purine and pyrimidine syntheses, methotrexate-resistant primary central nervous system lymphoma cell lines exhibited dysregulated expression of thymidylate synthetase, folylpolyglutamate synthetase, and methylenetetrahydrofolate dehydrogenase 1, which further influenced DNA synthesis [90]. Nagel et al denoted the changes in O 6 -methylguanine DNA methyltransferase contributed to the acquired chemoresistance of temozolomide in glioblastoma multiforme [91].…”

Section: Nucleotide Metabolismmentioning

confidence: 99%

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Guo

Tan

Chen

et al. 2020

Cancers

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Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Section: Nucleotide Metabolismmentioning

confidence: 99%

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Guo

Tan

Chen

et al. 2020

Cancers

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confidence: 99%

“…cell-type-specific intrinsic alterations and potential chemotherapies in NHL cell lines 13 . The 50% inhibition concentration (IC 50 ) for MTX in MTX-resistant PCNSL cell line HKBML (HKBML-MTX) is markedly higher than that in MTX-resistant PCNSL cell line TK (TK-MTX) and MTX-resistant systemic diffuse large B-cell lymphoma (DLBCL) cell line Raji (Raji-MTX) 13 . Conversely, sensitivity to a molecular targeted drug, bortezomib (26 S proteasome inhibitor) is observed in TK-MTX, but not in HKBML-MTX and Raji-MTX, with expression changes of MTX and folate metabolism including GGH, DHFR, FPGS, thymidylate synthase (TYMS), and MTHFD1 13 .…”

mentioning

confidence: 99%

“…The 50% inhibition concentration (IC 50 ) for MTX in MTX-resistant PCNSL cell line HKBML (HKBML-MTX) is markedly higher than that in MTX-resistant PCNSL cell line TK (TK-MTX) and MTX-resistant systemic diffuse large B-cell lymphoma (DLBCL) cell line Raji (Raji-MTX) 13 . Conversely, sensitivity to a molecular targeted drug, bortezomib (26 S proteasome inhibitor) is observed in TK-MTX, but not in HKBML-MTX and Raji-MTX, with expression changes of MTX and folate metabolism including GGH, DHFR, FPGS, thymidylate synthase (TYMS), and MTHFD1 13 . Although MTX-resistance-agitated global expression and signaling pathway changes associated with patient prognoses have not yet been elucidated, recent studies are gradually revealing cell-type specificities between HKBML and TK [13][14][15] .…”

mentioning

confidence: 99%

“…Conversely, sensitivity to a molecular targeted drug, bortezomib (26 S proteasome inhibitor) is observed in TK-MTX, but not in HKBML-MTX and Raji-MTX, with expression changes of MTX and folate metabolism including GGH, DHFR, FPGS, thymidylate synthase (TYMS), and MTHFD1 13 . Although MTX-resistance-agitated global expression and signaling pathway changes associated with patient prognoses have not yet been elucidated, recent studies are gradually revealing cell-type specificities between HKBML and TK [13][14][15] . PCNSL is heterogenous and distinct from non-CNS DLBCL in compositions of immune cells including T and dendritic cells.…”

mentioning

confidence: 99%

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GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Takashima¹,

Hamano

Fukai

et al. 2020

Sci Rep

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Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin's B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. these results suggest that the GSeA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances. Primary central nervous system lymphoma (PCNSL) is a rare subtype of cerebral malignant non-Hodgkin's B-cell lymphoma with a median overall survival (OS) of approximately four years, which accounts for 3% of all primary brain tumors and 1% of non-Hodgkin's lymphomas (NHLs) in adults 1,2. Methotrexate (MTX) is an antifolate that inhibits dihydrofolate (DHF) reductase (DHFR) activity in purine and thymidine syntheses and regulates the expression of glucocorticoid receptors α and β in human blood cells in vitro 3,4. High-dose MTX (HD-MTX) is used as a first-line treatment in PCNSL 5. Second-line treatments are also required for 10-35% of patients with refractory diseases and for another 35-60% or more who have relapse-acquired MTX resistances 6. Thus, almost PCNSLs recur with MTX resistances despite standard treatments 7. MTX is an antifolate that inhibits DNA synthesis 4. DHFR converts DHF to tetrahydrofolate (THF), a basic form of reduced folate coenzymes 8. MTX resistances are acquired through alternative intrinsic mechanisms in malignant cells, which include decreased drug transport due to mutations and reduced transcription activity of folate carrier genes, dysregulated DHFR activity and affinity, and decreased polyglutamination of MTX due to decreased folylpolyglutamate synthetase (FPGS) activity and increased γ-glutamyl hydrolase (GGH) activity 9-11. MTX exposure induces the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocystein...

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Target enzymes in serine‐glycine‐one‐carbon metabolic pathway for cancer therapy

Sun

Zhao

Cui

2022

Intl Journal of Cancer

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Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one-carbon units for nucleotide biosynthesis. In this process, serine-glycine metabolism and the onecarbon cycle play vital roles, which is named serine-glycine-one-carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate-mediated one-carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use onecarbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors.

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

Cited by 7 publications

References 41 publications

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Target enzymes in serine‐glycine‐one‐carbon metabolic pathway for cancer therapy

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