Tirapazamine is an anti-tumor agent showing cytotoxicity effect on A549, HT-29, SW620 and MDA-MB-468 cell in hypoxia condition with IC50 values of 6.8, 9.45, 1.2 and 1.304μM respectively[1][2]. Tirapazamine is converted by intercellular reductase to reactive radical species that can cause single- or double- strand DNA damage, and this reaction can be reversed under aerobic conditions. Tirapazamine is preferentially activated in solid tumors, which are characterized by a hypoxic environment[3]. Recognized as a commonly used bioreductive anticancer drug, Tirapazamine is extensively applied in the treatment of various cancer types, including hepatocellular carcinoma, colorectal carcinoma, and small cell lung cancer. Additionally, Tirapazamine is reported bactericidal and more active under anaerobic conditions, which reveals its potential as a antibacterial agents[4].
In vitro, Tirapazamine induces a dose-dependent increase in cell apoptosis under hypoxic conditions in murine C26 and MC38 colorectal carcinoma cells after a 24-hour treatment with concentrations ranging from 0 to 40μM, through the activation of caspase-3 cleavage[5]. Tirapazamine has been shown to inhibit the accumulation of HIF-1α in HeLa cells when exposed to a concentration of 20μM for 4 hours, an effect attributed to the reduction in HIF-1α protein synthesis via the phosphorylation of eIF2α[6]. Tirapazamine’s cytotoxic effect on LXFL 529 human lung carcinoma cells, within a concentration range of 0 to 100μM and a treatment duration of 1 hour, is mediated through topoisomerase II. This mediation occurs by stabilizing DNA-topoisomerase II complexes, resulting in the formation of DNA double-strand breaks (DSBs)[7].
In vivo, Tirapazamine was used to treat E.coli infected BALB/c mice by intraperitoneally adiministration at dosage of 25mg/kg, twice daily for 7 days, resulting in significant antibacterial activity and a prolonged survival period for the animal model[4]. Intraperitoneally administration of Tirapazamine (30mg/kg every 2 days) inhibited the tumor growth in HepG2 xenograft mouse model. Tirapazamine administration was observed to decrease the expression level of HIF-1α protein and increase p-eIF2α-positive staining in tumor tissues[6]. Tirapazamine (5,10mg/kg) was intraperitoneally injected into Wistar rats once a week for six weeks in combination with Doxorubicin (1.8mg/kg). Tirapazamine shows protective effect on rat myocardium by reduce oxidative stress and RyR2 protein level disturbed by Doxorubicin[8].
References:
[1] Cheng WY,Yuan YT, Ni Qiu N,et al.Identification of novel 4-anilinoquinazoline derivatives as potent EGFR inhibitors both under normoxia and hypoxia.Bioorganic & Medicinal Chemistry. 2014 Dec15,22(24):6796-6805
[2] Sansom N.G.,Kirk S.N.,Guise P.C.,et al.Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study.Bioorg Med Chem Lett. 2019 May 15;29(10):1215-1219.
[3] Gandara R.D, Lara N.P.Jr,Goldberg Z,et al.Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.Semin Oncol.2002 Feb;29(1 Suppl 4):102-9.
[4] Wu ZH,Wang Y,Li L,et al.New insights into the antimicrobial action and protective therapeutic effect of tirapazamine towards Escherichia coli-infected mice.Int J Antimicrob Agents. 2023 Sep;62(3):106923.
[5] Govaert K.M.,Nijkamp M.W.,Emmink B.L.,et al.Effects of tirapazamine on experimental colorectal liver metastases after radiofrequency ablation.Br J Surg.2012 Apr;99(4):567-75.
[6] Zhang J, Cao J, Weng QJ, et al.Suppression of hypoxia-inducible factor 1α (HIF-1α) by tirapazamine is dependent on eIF2α phosphorylation rather than the mTORC1/4E-BP1 pathway.PLoS One. 2010 Nov 9;5(11):e13910.
[7] Peters, K.B, Brown J.M.,Tirapazamine: a hypoxia-activated topoisomerase II poison.Cancer Res.2002 Sep 15;62(18):5248-53.
[8] Sliwinska J, et al. Tirapazamine-doxorubicin interaction referring to heart oxidative stress and Ca2+ balance protein levels. Oxid Med Cell Longev. 2012;2012:890826.
Tirapazamine是一种抗肿瘤药物，对缺氧状态下的A549、HT-29、SW620和MDA-MB-468细胞具有细胞毒性作用，IC50值分别为6.8、9.45、1.2和1.304μM[1][2]。Tirapazamine通过细胞还原酶转化为可引起单链或双链DNA损伤的活性自由基，并且该反应可在有氧条件下逆转。Tirapazamine在以缺氧环境为特征的实体肿瘤中优先被激活[3]。Tirapazamine是一种常用的生物还原性抗癌药物，广泛应用于肝细胞癌、结直肠癌、小细胞肺癌等多种类型癌症的治疗。Tirapazamine具有杀菌作用，在厌氧条件下更有活性，这显示了它作为抗菌药物的潜力[4]。
在体外，在缺氧环境下，使用0-40μM的Tirapazamine处理小鼠C26和MC38结直肠癌细胞24小时，Tirapazamine通过激活caspase-3切割剂量依赖性地诱导癌细胞凋亡[5]。当暴露于20μM的Tirapazamine 4小时，Tirapazamine可以通过磷酸化eIF2α和减少HIF-1α蛋白的合成从而抑制HeLa细胞中HIF-1α蛋白的积累[6]。此外，Tirapazamine（0-100μM, 1h）对LXFL 529人肺癌细胞的细胞毒性作用是通过topoisomerase II介导的，Tirapazamine稳定DNA-topoisomerase II复合物，从而导致DNA双链断裂（DSB）的形成[7]。
在体内，Tirapazamine （25mg/kg; i.p.; twice daily for 7 days）治疗大肠杆菌感染的BALB/c小鼠。Tirapazamine在动物模型中有明显的抗菌作用，并延长了感染小鼠的生存期[4]。腹腔注射Tirapazamine（30mg/kg/2 days）可通过降低肿瘤组织中HIF-1α蛋白表达水平，增加p-eIF2α阳性染色，从而抑制HepG2异种移植小鼠模型的肿瘤生长[6]。Tirapazamine（5 or 10mg/kg）联合Doxorubicin（1.8mg/kg）腹腔注射Wistar大鼠，每周1次，连用6周后发现Tirapazamine可以通过减少Doxorubicin引起的氧化应激和RyR2蛋白水平紊乱对大鼠心肌起到保护作用[8]