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Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
Published on: December 2, 2022
YM155 inhibits topoisomerase function
Mei Hong1, Ming-Qiang Ren, Jeane Silva
1aCancer Center, Georgia Regents University Cancer Center bDepartment of Surgery cDepartment of ENT Surgery, Center for Biotechnology and Genomic Medicine dDepartment of Medicine, Medical College of Georgia, Augusta eDepartment of Chemistry, Georgia State University, Atlanta, Georgia, USA.
Abstract:
YM155 (sepantronium bromide) has been evaluated in clinical trials as a survivin suppressant, but despite positive signals from early work, later studies were negative. Clarification of the mechanism of action of YM155 is important for its further development. YM155 affects cells in a cell cycle-specific manner. When cells are in G1, YM155 prevented their progression through the S phase, leaving the cells at G1/S when exposed to YM155. Passage through mitosis from G2 is also defective following YM155 exposure. In this study, YM155 did not behave like a typical DNA intercalator in viscosity, circular dichroism, and absorption spectroscopy studies. In addition, molecular modeling experiments ruled out YM155 DNA interaction to produce DNA intercalation. We show that YM155 inhibited topoisomerase 2α decatenation and topoisomerase 1-mediated cleavage of DNA, suggesting that YM155 inhibits the enzyme function. Consistent with these findings, DNA double-strand break repair was also inhibited by YM155.
Insights
YM155 (sepantronium bromide) inhibits DNA topoisomerase activity, impacting cell cycle progression and DNA repair. This clarifies its mechanism, crucial for developing YM155 as a cancer therapeutic.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- YM155 (sepantronium bromide) is a survivin suppressant evaluated in clinical trials.
- Despite early promise, later clinical studies of YM155 yielded negative results.
- Understanding YM155's precise mechanism of action is critical for its therapeutic development.
Purpose of the Study:
- To elucidate the mechanism of action of YM155.
- To investigate YM155's interaction with DNA and its effect on DNA-related enzymes.
- To determine if YM155 functions as a DNA intercalator.
Main Methods:
- Viscosity, circular dichroism, and absorption spectroscopy were used to assess DNA interaction.
- Molecular modeling was employed to rule out DNA intercalation.
- Inhibition of topoisomerase 2α decatenation and topoisomerase 1-mediated DNA cleavage was measured.
- Effects on DNA double-strand break repair were assessed.
Main Results:
- YM155 did not exhibit characteristics of a typical DNA intercalator.
- Molecular modeling excluded YM155-induced DNA intercalation.
- YM155 was found to inhibit the enzymatic function of topoisomerase 2α and topoisomerase 1.
- YM155 treatment resulted in the inhibition of DNA double-strand break repair.
- YM155 induced cell cycle arrest at the G1/S phase and impaired mitotic progression.
Conclusions:
- YM155's mechanism of action involves the inhibition of topoisomerase enzymes, not DNA intercalation.
- Inhibition of topoisomerases by YM155 leads to impaired DNA repair and cell cycle disruption.
- These findings provide a clearer understanding of YM155's effects, guiding future therapeutic strategies.
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