Hasinoff Brian B, Wu Xing, Patel Daywin, Kanagasabai Ragu, Karmahapatra Soumendrakrishna, Yalowich Jack C
College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.).
J Pharmacol Exp Ther. 2016 Feb;356(2):397-409. doi: 10.1124/jpet.115.228650. Epub 2015 Dec 11.
Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIα as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phospho-histone γH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzyme-to-DNA assay; and to display cross-resistance in etoposide-resistant K562 cells. Pixantrone produced semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake. Pixantrone was 10- to 12-fold less damaging to neonatal rat myocytes than doxorubicin or mitoxantrone, as measured by lactate dehydrogenase release. Three factors potentially contribute to the reduced cardiotoxicity of pixantrone. First, its lack of binding to iron(III) makes it unable to induce iron-based oxidative stress. Second, its low cellular uptake may limit its ability to produce semiquinone free radicals and redox cycle. Finally, because the β isoform of topoisomerase II predominates in postmitotic cardiomyocytes, and pixantrone is demonstrated in this study to be selective for topoisomerase IIα in stabilizing enzyme-DNA covalent complexes, the attenuated cardiotoxicity of this agent may also be due to its selectivity for targeting topoisomerase IIα over topoisomerase IIβ.
匹杉琼是一种新型的无心脏毒性的氮杂蒽二酮类抗癌药物，其结构与蒽环类药物和蒽二酮类药物相关，如多柔比星和米托蒽醌。匹杉琼在欧盟被批准用于治疗复发或难治性侵袭性B细胞非霍奇金淋巴瘤。本研究旨在探究其抗癌活性机制及其相对缺乏心脏毒性的原因。匹杉琼靶向DNA拓扑异构酶IIα，这可通过其抑制动质体DNA解连环的能力得以证明；在pBR322 DNA切割试验中产生线性双链DNA；在细胞磷酸化组蛋白γH2AX试验中产生DNA双链断裂；在细胞酶 - DNA复合物免疫检测中形成共价拓扑异构酶II - DNA复合物；以及在依托泊苷耐药的K562细胞中表现出交叉耐药性。匹杉琼在酶促还原系统中产生半醌自由基，但在细胞系统中不产生，这很可能是由于细胞摄取率低所致。通过乳酸脱氢酶释放量测定，匹杉琼对新生大鼠心肌细胞的损伤比多柔比星或米托蒽醌小10至12倍。有三个因素可能导致匹杉琼心脏毒性降低。首先，它不与铁（III）结合，使其无法诱导基于铁的氧化应激。其次，其低细胞摄取率可能限制了其产生半醌自由基和氧化还原循环的能力。最后，由于拓扑异构酶II的β同工型在有丝分裂后心肌细胞中占主导地位，并且本研究表明匹杉琼在稳定酶 - DNA共价复合物方面对拓扑异构酶IIα具有选择性，该药物心脏毒性减弱也可能是由于其对拓扑异构酶IIα的靶向选择性高于拓扑异构酶IIβ。
