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Timing Is Everything: Misincorporation of 8oxodG during Mitosis Is Lethal

Khadijeh Alnajjar1, Joann B Sweasy2

  • 1Department of Cellular and Molecular Medicine and University of Arizona Cancer Center, Tucson, Arizona.

Cancer Research
|September 4, 2020
PubMed

Insights

This study reveals that the inhibitor TH588 boosts reactive oxygen species in cancer cells during mitosis. It disrupts cell division and DNA repair, leading to increased cancer cell toxicity and potential new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted cancer therapies often exploit universal vulnerabilities in cancer cells.
  • Reactive oxygen species (ROS) play a complex role in cancer progression and treatment response.

Purpose of the Study:

  • To elucidate the mechanism of the dual-functioning inhibitor TH588 in cancer cells.
  • To understand how TH588 affects mitotic progression and DNA integrity.

Main Methods:

  • Investigated the effects of TH588 on cancer cells during mitosis.
  • Assessed the impact of TH588 on reactive oxygen species accumulation.
  • Analyzed the inhibition of 8-oxoguanosine triphosphate (8-oxodGTP) hydrolysis and 8-oxoguanosine (8-oxodG) incorporation into DNA.

Main Results:

  • TH588 potentiates ROS accumulation during mitosis by disturbing mitotic progression.
  • TH588 inhibits the hydrolysis of 8-oxodGTP, leading to increased 8-oxodG incorporation into DNA during mitotic replication.
  • This dual action results in increased DNA damage and cancer cell toxicity.

Conclusions:

  • The dual-functioning inhibitor TH588 exhibits anti-cancer activity by inducing oxidative stress and DNA damage during mitosis.
  • Understanding TH588's mechanism provides a foundation for identifying novel cancer targets and developing new therapeutic strategies.

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