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Anticancer effect of (S)-crizotinib on osteosarcoma cells by targeting MTH1 and activating reactive oxygen species

Xiangcheng Qing1, Zengwu Shao1, Xiao Lv1

  • 1Departments of Orthopedics.

Anti-Cancer Drugs
|February 9, 2018
PubMed

Insights

MTH1 (mut Tpase 1) is highly expressed in osteosarcoma (OS). Targeting MTH1 with (S)-crizotinib inhibits OS cell proliferation and migration by activating reactive oxygen species (ROS).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • MTH1 (mut Tpase 1) is a key target in cancer therapy, particularly for 'cancer phenotypic lethality'.
  • Osteosarcoma (OS) is a common bone cancer with limited treatment options, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the anticancer effects of the MTH1-targeted drug (S)-crizotinib on osteosarcoma (OS) cells.
  • To explore the role of MTH1 expression in OS development and its potential as a therapeutic target.

Main Methods:

  • Immunohistochemistry and western blot to detect MTH1 expression in OS tissues and cells.
  • siRNA technology and CCK8 assays to assess MTH1's effect on OS cell viability.
  • In-vitro assays to evaluate (S)-crizotinib's efficacy, including apoptosis, cell cycle arrest, and migration.
  • Detection of intracellular 8-oxo-dGTP levels and reactive oxygen species (ROS) using specific staining methods.

Main Results:

  • MTH1 expression was significantly elevated in OS tissues and cell lines compared to normal controls.
  • Knockdown of MTH1 using siRNA suppressed OS cell proliferation.
  • (S)-Crizotinib inhibited OS cell proliferation, induced apoptosis, caused G0/G1 cell cycle arrest, and suppressed migration.
  • The anticancer effects of (S)-crizotinib were mediated by targeting MTH1 and activating ROS.

Conclusions:

  • MTH1 is a promising therapeutic target for osteosarcoma.
  • (S)-Crizotinib demonstrates significant anticancer potential against OS by modulating MTH1 and ROS.
  • This study provides a strong theoretical basis for the clinical application of (S)-crizotinib in treating osteosarcoma.

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