Mitoxantrone, More than Just Another Topoisomerase II Poison

Abstract

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.

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

“…Camptothecin induces DNA damage by inhibiting topoisomerase I 45 , and mitoxantrone is a topoisomerase II poison 46 . As shown in Supplementary Fig.…”

Anticancer metal drugs and immunogenic cell death

“…Anthracyclines (doxorubicin, epirubicin, idarubicin), commonly used antibiotics against a wide panel of tumors in the clinics, are considered prototypic ICD inducers transferring immunostimulatory potential based on activation of all ICD hallmark features in diverse cancer cell types [36] and in the absence of any adjuvant [37]. Mitoxantrone, as an anthracendione, is a structurally related DNA-intercalating compound clinically used for treatment of acute myeloid leukemia, non-Hodgkin's lymphoma and several solid tumors including breast and prostate cancer [38]. ICD induction by mitoxantrone in combination with an oncolytic virus was recently demonstrated to overcome immunologic tolerance established toward cancer antigens [39].…”

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

“…Oxidative activation of TOP2 poisons is not limited to etoposide because MPO has been implicated in the activation of mitoxantrone either directly or via the production of reactive aldehydes (Panousis et al, 1995, 1997; Hazen et al, 1998; Parker et al, 1999; Evison et al, 2016). …”