Mitoxantrone作为一种有效的拓扑异构酶II抑制剂,它可以抑制DNA复制,同时它是一种线粒体钙单转运蛋白(MCU)抑制剂,它还能抑制蛋白激酶C (PKC)活性,IC50为8.5 μM。.
Mitoxantrone is an antitumor anthrandione derivative. As a potent inhibitor of topoisomerase II, Mitoxantrone can inhibit DNA replication and induce single and double strand breaks through hydrogen bond insertion into DNA. Mitoxantrone is an inhibitor of mitochondrial calcium monotransporter (MCU), which can inhibit calcium entering into mitochondria and prevent mitochondrial calcium overload [1-3]. Mitoxantrone also inhibits protein kinase C (PKC) activity with an IC50 of 8.5 μM.
Mitoxantrone(0.5μg/ml; 48h) induced DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), the cytotoxic effect of mitoxantrone was due to induction of apoptosis[4]. Mitoxantrone (50 nM; 24 h) reduced the triglyceride (TG) levels and total cholesterol levels in LMH cells(a steatosis cell model). Mitoxantrone improves hepatic steatosis in broilers as well as reduces circulating lipid levels and fat accumulation in broilers[5].
After mitoxantrone treatment(0-3.2 mg/kg/day; i.p; on days 1, 5, and 9 following tumor inoculation), the increase life span (ILS) of tumor-bearing mice increased by more than 100%[6]. Mitoxantrone persistently suppresses B cells in vivo and led to an enrichment of neutrophils and immunomodulatory CD8(low) T cells[7].
参考文献:
[1]. Nathanson L. Mitoxantrone. Cancer Treat Rev. 1984 Dec;11(4):289-93. doi: 10.1016/0305-7372(84)90025-2. PMID: 6534511.
[2]. Durr FE, Wallace RE, et,al. Molecular and biochemical pharmacology of mitoxantrone. Cancer Treat Rev. 1983 Dec;10 Suppl B:3-11. doi: 10.1016/0305-7372(83)90016-6. PMID: 6362876.
[3]. Arduino DM, Wettmarshausen J, et,al. Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening. Mol Cell. 2017 Aug 17;67(4):711-723.e7. doi: 10.1016/j.molcel.2017.07.019. PMID: 28820965; PMCID: PMC5825229.
[4]. Bellosillo B, Colomer D, et,al. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 1998 Jan;100(1):142-6. doi: 10.1046/j.1365-2141.1998.00520.x. PMID: 9450803.
[5]. Vibet S, Mahéo K, et,al. Differential subcellular distribution of mitoxantrone in relation to chemosensitization in two human breast cancer cell lines. Drug Metab Dispos. 2007 May;35(5):822-8. doi: 10.1124/dmd.106.013474. Epub 2007 Feb 12. PMID: 17296624.
[6]. Fujimoto S, Ogawa M. Antitumor activity of mitoxantrone against murine experimental tumors: comparative analysis against various antitumor antibiotics. Cancer Chemother Pharmacol. 1982;8(2):157-62. doi: 10.1007/BF00255476. PMID: 7105379.
[7]. Chanvillard C, Millward JM, et,al. Mitoxantrone induces natural killer cell maturation in patients with secondary progressive multiple sclerosis. PLoS One. 2012;7(6):e39625. doi: 10.1371/journal.pone.0039625. Epub 2012 Jun 29. PMID: 22768101; PMCID: PMC3387260.
米托蒽醌Mitoxantrone是一种抗肿瘤的蒽醌衍生物。作为一种有效的拓扑异构酶II抑制剂,Mitoxantrone可以抑制DNA复制,通过氢键插入DNA诱导单链和双链断裂。Mitoxantrone也是一种线粒体钙单转运体(MCU)抑制剂,可以抑制钙进入线粒体,防止线粒体钙超载[1-3]。
Mitoxantrone (0.5μg/ml; 48h)诱导DNA断裂和聚腺苷核糖聚合酶(PARP)的蛋白水解裂解,其细胞毒作用是由于诱导细胞凋亡所致[4]。Mitoxantrone (50 nM; 24 h)降低了LMH细胞(脂肪变性细胞模型)中的甘油三酯(TG)水平和总胆固醇水平。Mitoxantrone改善肉仔鸡肝脏脂肪变性,降低肉仔鸡循环脂质水平和脂肪积累[5]。
经Mitoxantrone治疗(0-3.2 mg/kg/day; i.p; on days 1, 5, and 9 following tumor inoculation)后,荷瘤小鼠的延长寿命(ILS)提高100%以上[6]。Mitoxantrone在体内持续抑制B细胞,导致中性粒细胞和免疫调节性CD8(低)T细胞的富集[7]。
| Cell experiment [1]: | |
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Cell lines |
B-chronic lymphocytic leukaemia (B-CLL) cells |
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Preparation Method |
Cells were incubated for 48 h with 0.5 μg/ml mitoxantrone. |
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Reaction Conditions |
0.5μg/ml; 48h |
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Applications |
Mitoxantrone induces apoptosis in B-CLL lymphocytes. |
| Animal experiment [2]: | |
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Animal models |
BDF female mice (L1210 cell tumor model) |
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Preparation Method |
The drugs were given IP or IV, in general on days 1, 5, and 9 following tumor inoculation. |
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Dosage form |
0-3.2 mg/kg/day; i.p; on days 1, 5, and 9 following tumor inoculation |
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Applications |
The increase life span (ILS) of tumor-bearing mice increased by more than 100% after intravenous administration of mitoxantrone. |
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参考文献: [1]. Bellosillo B, Colomer D, et,al. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 1998 Jan;100(1):142-6. doi: 10.1046/j.1365-2141.1998.00520.x. PMID: 9450803. | |
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