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Human Glioma Cells Acquire Temozolomide Resistance After Repeated Drug Exposure Via DNA Mismatch Repair Dysfunction

Kei Yamashiro1, Kazutaka Nakao1, Shigeo Ohba1

  • 1Department of Neurosurgery, Fujita Health University, Toyoake, Japan.

Anticancer Research
|March 6, 2020
PubMed
Abstract

Insights

Longer exposure to temozolomide (TMZ) can lead to drug resistance in glioma cells by altering DNA repair mechanisms, specifically reducing MSH6 expression. G2 checkpoint inhibitors did not restore sensitivity in resistant cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Temozolomide (TMZ) is a standard chemotherapy agent for gliomas.
  • TMZ induces cell cycle arrest at the G2/M phase, which is crucial for its efficacy.
  • The G2 checkpoint plays a role in DNA damage response and repair.

Purpose of the Study:

  • To investigate the mechanisms underlying temozolomide resistance in human glioma cells.
  • To determine the role of the G2 checkpoint in acquired TMZ resistance.
  • To explore the potential of G2 checkpoint inhibitors in overcoming TMZ resistance.

Main Methods:

  • Established temozolomide-resistant (TR) U87MG glioma cell clones through serial TMZ treatment.
  • Assessed TMZ-induced G2/M cell cycle arrest in short-term and long-term treated clones.
  • Evaluated the effect of G2 checkpoint inhibitors on TMZ sensitivity in TR clones.
  • Measured MSH6 expression levels in TR clones.

Main Results:

  • Long-term TMZ exposure (over 6 months) resulted in TR clones with significantly reduced G2/M arrest compared to short-term exposure (4 months).
  • MSH6 expression was decreased in long-term TR clones.
  • G2 checkpoint inhibitors failed to resensitize the established TR clones to temozolomide.

Conclusions:

  • Prolonged temozolomide treatment can induce resistance in glioma cells.
  • This resistance appears to be mediated by modifications in DNA repair pathways, potentially involving MSH6.
  • The G2 checkpoint may not be a viable target for overcoming established temozolomide resistance.
Keywords:
DNA mismatch repairG2 checkpointTemozolomideglioblastomaresistance

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