Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II

Biochemical Pharmacology
Ka C LeeCaroline A Austin

Abstract

The reaction mechanism of DNA topoisomerase II (TOP2) involves a covalent double-strand break intermediate in which the enzyme is coupled to DNA via a 5'-phosphotyrosyl bond. This normally transient enzyme-bridged break is stabilised by drugs such as mitoxantrone, mAMSA, etoposide, doxorubicin, epirubicin and idarubicin, which are referred to as TOP2 poisons. Removal of topoisomerase II by the proteasome is involved in the repair of these lesions. In K562 cells, inhibiting the proteasome with MG132 significantly potentiated the growth inhibition by these six drugs that target topoisomerase II, and the highest level of potentiation was observed with mitoxantrone. Mitoxantrone also showed the greatest potentiation by MG132 in three Nalm 6 cell lines with differing levels of TOP2A or TOP2B. Mitoxantrone was also potentiated by the clinically used proteasome inhibitor PS341 (Velcade). We have also shown that proteasome inhibition with MG132 in K562 cells reduces the rate of removal of mitoxantrone or etoposide stabilised topoisomerase complexes from DNA, suggesting a possible mechanism for the potentiation of topoisomerase II drugs by proteasomal inhibition.

References

Jun 19, 1998·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·C A Austin, K L Marsh
Oct 28, 1998·Trends in Cell Biology·D H Lee, A L Goldberg
Sep 8, 2001·The Journal of Biological Chemistry·Y MaoL F Liu
Mar 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Hai XiaoLeroy F Liu
Jul 5, 2006·Molecular Cancer Therapeutics·Mobeen MalikJohn L Nitiss
Sep 16, 2006·The Journal of Biological Chemistry·Ailing ZhangLeroy F Liu
May 26, 2007·Science·Bijan SobhianRoger A Greenberg
Aug 3, 2007·Cancer Research·Céline Jacquemont, Toshiyasu Taniguchi
Oct 25, 2007·PloS One·Ian G CowellMichael J Tilby
Dec 29, 2007·Antioxidants & Redox Signaling·Hirokuni ShinagawaKiyotsugu Yoshida
May 22, 2008·Expert Opinion on Investigational Drugs·Jan SterzOrhan Sezer
Jul 29, 2008·Current Opinion in Chemical Biology·Bradley S MooreRyan P McGlinchey
Aug 22, 2009·Biochemical and Biophysical Research Communications·Jisoo YunCheol-Hee Choi
Sep 18, 2010·Journal of Nucleic Acids·Nicola J SunterCaroline A Austin
Jan 22, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Mei-Chuan ChenChing-Shih Chen
Oct 30, 2012·Nature Structural & Molecular Biology·Matthew J SchellenbergR Scott Williams
Dec 6, 2012·Biology Open·Ka Cheong LeeCaroline A Austin
Dec 28, 2012·Cell Division·Namrata Rastogi, Durga Prasad Mishra

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Citations

Jul 18, 2018·International Journal of Molecular Sciences·Ka Cheong LeeCaroline A Austin
Sep 19, 2018·International Journal of Molecular Sciences·Caroline A AustinIan G Cowell
Apr 8, 2020·Future Oncology·Sayantani RoychoudhuryNilesh Kumar Sharma
May 2, 2020·Nucleic Acids Research·Matthew J SchellenbergR Scott Williams
Jun 27, 2020·Molecular Pharmacology·Rebecca L SwanCaroline A Austin
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Una GlamočlijaDavorka Završnik
Aug 11, 2019·Molecular Pharmacology·Mandeep AtwalCaroline A Austin
Jul 14, 2020·Frontiers in Cellular and Infection Microbiology·Sergio O AngelWilliam J Sullivan
Mar 17, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Piotr StrusIzabela Mlynarczuk-Bialy
May 5, 2021·Molecular Pharmacology·Rebecca L SwanCaroline A Austin
Oct 9, 2019·Journal of Medicinal Chemistry·Žiga SkokJanez Ilaš
Nov 9, 2021·Biochemical Society Transactions·Caroline A AustinHuei Teng Ng
Oct 25, 2021·Molecular Pharmacology·Rebecca L SwanCaroline A Austin

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