PixantronePixantrone
MedChemExpress (MCE)
HY-13727A
144675-97-8
BBR 2778
98.75%
4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months
-20°C, 1 month (sealed storage, away from moisture)
Room temperature in continental US
may vary elsewhere.
Pixantrone (BBR 2778) dimaleate is a topoisomerase II inhibitor and DNA intercalator, with anti-tumor activity.
Pixantrone (0-10 μM, 72 h) dimaleate induces cell death in multiple cancer cell lines independent of cell cycle perturbation, with IC50s of 37.3 nM, 126 nM and 136 nM for T47D, MCF-10A and OVCAR5 cells, respectively[1]. Pixantrone (25-500 nM, 2 4 h) dimaleate induces DNA damage at high concentration of 500 nM and induces severe chromosomal aberrations and mitotic catastrophe in PANC1 cells[1]. Pixantrone (100 nM, 24 h) dimaleate may disrupt chromosome segregation because of generating merotelic kinetochore attachments that cause chromosome non-disjunction[1]. Pixantrone (0-100 μM, 72 h) dimaleate potently inhibits growth of human leukemia K562 cells, etoposide-resistant K/VP.5 cells, MDCK and ABCB1-transfected MDCK/MDR cells with IC50s of 0.10 μM, 0.56 μM, 0.058 μM and 4.5 μM, respectively[2]. Pixantrone (0.01-0.2 μM) dimaleate leads to a concentration-dependent formation of linear DNA through acting on topoisomerase Iiα and produces semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake[2]. Pixantrone (0.01-10 μM) dimaleate shows potent inhibitory activities against rat 97-116 peptide-specific T cell proliferation[4].
Pixantrone (i.v., 27 mg/kg, every 7 days, three times) dimaleate does not worsen pre-existing moderate degenerative cardiomyopathy, causes minimal cardiotoxic in mice following repeated treatment cycles and results in less mortality than Mitoxantrone (HY-13502) in Doxorubicin (HY-15142A)-pretreated mice[3]. Pixantrone (i.v., 16.25 mg/kg, every week, three times) dimaleate modulates Lymph node cells (LNC) responses, affacts T cell subpopulations in TAChR-immunized Lewis rats and also shows preventive and therapeutic effect in experimental autoimmune myasthenia gravis (EAMG) rats[4].
Mice[3] To evaluate the potential cardiotoxicity of Pixantrone in doxorubicin-pretreated mice, doxorubicin 7.5 mg/kg is administered intravenously every 7 days for 3 weeks (1 cycle) to a group of CD1 females. Six weeks later, these mice receive either 0.9% saline (vehicle), doxorubicin 7.5 mg/kg, Pixantrone 27 mg/kg, or mitoxantrone 3 mg/kg intravenously every 7 days for 3 weeks (2 cycles). Animals are sacrificed after the first cycle at 8 weeks, and after the second cycle at 16 weeks. In addition, to evaluate the potential cardiotoxicity of Pixantrone as a single agent compared with doxorubicin and mitoxantrone, CD1 female mice receive a single or a double cycle of vehicle, doxorubicin 7.5 mg/kg, Pixantrone 27 mg/kg, or mitoxantrone 3 mg/kg. These animals are sacrificed after the first and second cycles (at 8 and 16 weeks, all groups), during week 14 (Pixantrone-treated group only) and during week 22 (Pixantrone- and vehicle-treated groups)[3]. Rats[4] For the studies on Pixantrone efficacy on EAMG, TAChR-immunized rats are randomly assigned to different treatment groups: 1) preventive Pixantrone group, starting 4 days after immunization, with 16.25 mg/kg Pixantrone, administered i.v. via tail vein, once a week for three times
2) therapeutic Pixantrone group, starting 4 wk after immunization, with 16.25 mg/kg Pixantrone, administered i.v. via tail vein, once a week for three times
3) therapeutic MTX group (1.2 mg/kg, i.v. via tail vein, once a week for three times)
and 4) vehicle group (sterile saline, i.v. via tail vein, once a week for three times). The doses of Pixantrone and MTX used in this study are in both cases equal to one-fourth of the LD10 for single i.v. injection in rats. Treatment assignation is performed at day 4 after TAChR immunization (preventive schedule) in coincidence of the acute phase of EAMG, or at onset of clinical signs (therapeutic schedule), which occurs after 4 wk. Animals are sacrificed after deep anesthesia obtained by carbon dioxide
low-grade anesthesia with chloral hydrate administered i.p. is used for TAChR immunization and drug treatments[4].
Briefly, cells seeded into 96-well plates are treated with increasing concentrations of either pixantrone or doxorubicin for 72 hours. After this time, MTS reagent is added to cells and incubated at 37°C for a further 4 hours. Cell proliferation is then determined by measuring the absorbance at 490 nm. All data points are normalized to untreated cells. All treatments are performed in triplicate and performed a minimum of 3 times[1].
Topoisomerase II
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[1]. Beeharry N, et al. Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions. Cancer Biol Ther. 2015
16(9):1397-406. [Content Brief]
[2]. Hasinoff BB, et al. Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone
a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase IIα Isoform. J Pharmacol Exp Ther. 2016 Feb
356(2):397-409. [Content Brief]
[3]. Cavalletti E, et al. Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone. Invest New Drugs. 2007 Jun
25(3):187-95. [Content Brief]
[4]. Ubiali F, et al. Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats. J Immunol. 2008 Feb 15
180(4):2696-703. [Content Brief]
