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DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide

Mengting Zhao1, Biqin Tan2, Xiaoyang Dai1

  • 1Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

European Journal of Pharmacology
|September 23, 2019
PubMed

Insights

Dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS) promote glioma growth. Inhibiting DHFR/TYMS with pemetrexed synergizes with temozolomide (TMZ) chemotherapy, offering a new strategy for glioma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioma is a lethal brain malignancy with limited treatment options.
  • Resistance to temozolomide (TMZ) chemotherapy is a major challenge in glioma treatment.
  • Molecular drivers of gliomagenesis and TMZ resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS) in glioma.
  • To evaluate the potential of inhibiting DHFR/TYMS as a strategy to sensitize glioma cells to TMZ.
  • To elucidate the molecular mechanisms underlying the combined efficacy of DHFR/TYMS inhibition and TMZ.

Main Methods:

  • Analysis of DHFR and TYMS expression in human glioma tissues and cell lines.
  • In vitro and in vivo studies using glioma cell lines and U251 xenografts.
  • Pharmacological inhibition of DHFR/TYMS using pemetrexed in combination with TMZ.
  • Western blot analysis to assess the activation of AMPK and mTOR signaling pathways.

Main Results:

  • DHFR and TYMS were upregulated in glioma tissues and cell lines, promoting glioma cell proliferation.
  • Pemetrexed, an inhibitor of DHFR/TYMS, demonstrated synergistic anti-glioma activity with TMZ.
  • Combined treatment activated the AMPK signaling pathway and suppressed the mTOR signaling pathway.

Conclusions:

  • DHFR and TYMS play a significant role in glioma progression and TMZ resistance.
  • Inhibiting DHFR/TYMS with pemetrexed offers a promising synergistic approach with TMZ for glioma treatment.
  • The AMPK-mTOR pathway mediates the anti-glioma effects of combined DHFR/TYMS inhibition and TMZ therapy.
Keywords:
AMPK-mTORDHFRGliomaPemetrexedTYMSTemozolomide

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