Mitoxantrone, More than Just Another Topoisomerase II Poison.
Mitoxantrone is a synthetic anthracenedione originally developed to improve the therapeutic profile of the anthracyclines and is commonly applied in the treatment of breast and prostate cancers, lymphomas, and leukemias. A comprehensive overview of the drug's molecular, biochemical, and cellular pharmacology is presented here, beginning with the cardiotoxic nature of its predecessor doxorubicin and how these properties shaped the pharmacology of mitoxantrone itself. Although mitoxantrone is firmly established as a DNA topoisomerase II poison within mammalian cells, it is now clear that the drug interacts with a much broader range of biological macromolecules both covalently and noncovalently. Here, we consider each of these interactions in the context of their wider biological relevance to cancer therapy and highlight how they may be exploited to further enhance the therapeutic value of mitoxantrone. In doing so, it is now clear that mitoxantrone is more than just another topoisomerase II poison.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Victoria, 3086, Australia.
Benny J
BJ
Evison
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
Brad E
BE
Sleebs
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
Keith G
KG
Watson
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Victoria, 3086, Australia.
Don R
DR
Phillips
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Victoria, 3086, Australia.
Suzanne M
SM
Cutts
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008942:Mitoxantrone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D008942:Mitoxantrone
DNA adduct; DNA damage; mechanism of action; mitoxantrone; small molecule inhibitor; topoisomerase II