Mitoxantrone is a Topoisomerase II inhibitor, an anti-neoplastic drug for leukemia and other types of cancer, and a proven drug for multiple sclerosis.
Topoisomerase regulates and changes the topologic conditions of DNA during transcription. It plays a role in condensation of chromosome, separation of chromatid and the relief of torsional stress etc.
Mitoxantrone suppressed the leukemia via inhibiting DNA synthesis and cell cycle progression. It had effect on different immune cells (e.g. T cell, B cell and macrophage etc.) [1] It interfered with TOPO-II-mediated DNA cleavage and led to multiple DSB (DNA strand breaks), chromatin structure changes etc. [2] In PDA (pancreatic ductal adenocarcinoma) cell line, mitoxantrone affected cell survival with IC50 < 10 nM and targeted USP11 (human ubiquitin-specific peptidase 11). [3] In human dental pulp stem cells and human dermal fibroblasts, mitoxantrone induced apoptosis or premature senescence in a dose –dependent manner. [4]
In clinical trial, mitoxantrone exhibited a significant but partial efficacy in decreasing the chance of multiple sclerosis progression and relapses frequency in patient with worsening RRMS, PRMS and SPMS in a 2 years follow-up study. [5]
References:
[1] Fox EJ. Mechanism of action of mitoxantrone. Neurology. 2004 Dec 28;63(12 Suppl 6):S15-8.
[2] Awasthi P, Dogra S, Barthwal R. Multispectroscopic methods reveal different modes of interaction of anticancer drug mitoxantrone with Poly(dG-dC).Poly(dG-dC) and Poly(dA-dT).Poly(dA-dT). J Photochem Photobiol B. 2013 Oct 5;127:78-87.
[3] Burkhart RA, Peng Y, Norris ZA et al. Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. Mol Cancer Res. 2013 Aug;11(8):901-11.
[4] Seifrtova M, Havelek R, Soukup T, Filipova A, Mokry J, Rezacova M. Mitoxantrone ability to induce premature senescence in human dental pulp stem cells and human dermal fibroblasts. J Physiol Pharmacol. 2013 Apr;64(2):255-66.
[5] Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013 May 31;5:CD002127.