Mitoxantrone HCl

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.

Folic acid-conjugated TiO2-doped mesoporous carbonaceous nanocomposites loaded with Mitoxantrone HCl for chemo-photodynamic therapy.[Pubmed:25997891]

Photochem Photobiol Sci. 2015 Jun;14(6):1197-206.

Recently, porous carbons have showed great potential in many areas. In this study, TiO2-doped mesoporous carbonaceous (TiO2@C) nanoparticles were obtained by a simple one-pot hydrothermal treatment, folic acid (FA) was conjugated to TiO2@C through an amide bond, then Mitoxantrone HCl (MTX) was adsorbed onto TiO2@C-FA and a drug delivery system, TiO2@C-FA/MTX was obtained. TiO2@C-FA/MTX showed a much faster MTX release at pH 4.5 than at pH 6.0 and pH 7.4. Furthermore, compared with free MTX, this drug delivery system showed a dose-dependent cytotoxicity by varying the irradiance, and afforded higher antitumor efficacy in cultured PC3 cells in vitro. The ability of TiO2@C-FA/MTX to combine chemotherapy with photodynamic activity enhanced the cancer cell killing effect in vitro, demonstrating that TiO2@C-FA/MTX has a great potential for cancer therapy in the future.

Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival.[Pubmed:23696131]

Mol Cancer Res. 2013 Aug;11(8):901-11.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA. IMPLICATIONS: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA.

A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling.[Pubmed:23442188]

J Med Chem. 2013 Mar 28;56(6):2619-29.

The rational design of selective kinase inhibitors remains a great challenge. Here we describe a physics-based approach to computationally modeling the kinase inhibitor selectivity profile. We retrospectively assessed this protocol by computing the binding profiles of 17 well-known kinase inhibitors against 143 kinases. Next, we predicted the binding profile of the chemotherapy drug mitoxantrone, and chose the predicted top five kinase targets for in vitro kinase assays. Remarkably, mitoxantrone was shown to possess low nanomolar inhibitory activity against PIM1 kinase and to inhibit the PIM1-mediated phosphorylation in cancer cells. We further determined the crystal complex structure of PIM1 bound with mitoxantrone, which reveals the structural and mechanistic basis for a novel mode of PIM1 inhibition. Although mitoxantrone's mechanism of action had been originally thought to act through DNA intercalation and type II topoisomerase inhibition, we hypothesize that PIM1 kinase inhibition might also contribute to mitoxantrone's therapeutic efficacy and specificity.

Mitoxantrone: a review of its use in multiple sclerosis.[Pubmed:15089110]

CNS Drugs. 2004;18(6):379-96.

Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS. The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity. In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug. Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months' treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%. Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs. Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents. Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials. In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient. Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone. Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years' treatment). (ABSTRACT TRUNCATED)

Mitoxantrone affects topoisomerase activities in human breast cancer cells.[Pubmed:3010982]

Biochem Biophys Res Commun. 1986 Apr 29;136(2):521-8.

The effects of mitoxantrone, an antineoplastic DNA intercalator, on topoisomerase I and II were studied in two human breast cancer cell lines. A large increase of topoisomerase I activity was found when cells were exposed to various doses of mitoxantrone. Maximal effect was achieved with 20 and 40 ng/mL in T47D and MCF-7 cells respectively. The enhancement on topoisomerase I activity seemed to be reversible, to be dependent on time of exposure to the drug and to require cellular integrity. Type II topoisomerase was inhibited in T47D cells after treatment for one hour with 10 ng/mL of mitoxantrone and enzyme activity was undetectable at higher doses (40 ng/mL). This inhibitory effect did not take place in vitro unless the concentration of the intercalator was increased to 400-500 ng/mL.

Mitoxantrone dihydrochloride is a topoisomerase II inhibitor; also inhibits protein kinase C (PKC) activity with an IC50 of 8.5 μM.

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