Tumor-targeted induction of oxystress for cancer therapy
Tumor-targeted induction of oxystress for cancer therapy
复制标题
DOI：
10.1080/10611860701498286
复制
发表时间：
2007-01-01
影响因子：
4.5
通讯作者：
Iyer, A. K.
中科院分区：
文献类型：
--
作者：
Fang, J.;Nakamura, H.;Iyer, A. K.
活性氧（ROS），如超氧阴离子自由基（O-2（中心点-））和过氧化氢（H2 O2）是正常细胞代谢的潜在有害副产物，其直接影响细胞功能。ROS是由所有需氧生物产生的，它似乎是调节细胞生长和还原-氧化（氧化还原）状态的信号转导途径不可或缺的。然而，这些高活性氧代谢产物的过量产生会引发致命的连锁反应，这涉及对细胞完整性和生存至关重要的结构的氧化和损伤。事实上，许多抗肿瘤剂，如长春碱、顺铂、丝裂霉素C、多柔比星、喜树碱、inostamycin、新制癌素和许多其它抗肿瘤剂通过ROS依赖性激活凋亡细胞死亡而表现出抗肿瘤活性，这表明ROS作为抗肿瘤原理的潜在用途。因此，一种独特的抗癌策略，称为“氧化疗法”已开发通过诱导细胞毒性氧化应激用于癌症治疗。这一目标主要可以通过两种方法实现，即（i）直接诱导实体肿瘤产生ROS和（ii）抑制肿瘤细胞的抗氧化酶（防御）系统。自20世纪50年代以来，基于第一种方法，即向荷瘤动物施用ROS本身（例如H2 O2）或ROS产生酶，已经采用了许多策略。然而，没有获得成功和实际的结果，可能是因为缺乏肿瘤选择性ROS递送，因此导致随后诱导严重的副作用。为了克服这些障碍，我们开发了聚乙二醇（PEG）结合的O-2（中心点-）或H2 O2产生酶，黄嘌呤氧化酶（XO）和D-氨基酸氧化酶（DAO）（PEG-DAO）。最近，制备了聚乙二醇化（PEG）锌原卟啉（PEG-ZnPP）和基于两亲性苯乙烯马来酸（SMA）共聚物的高度水溶性ZnPP胶束制剂SMA-ZnPP，它们是血红素加氧酶-1（HO-1）的有效抑制剂。HO-1是肿瘤的主要抗氧化酶，其作用机制与过氧化氢酶或超氧化物歧化酶（SOD）不同。因此，PEG-酶和PEG-ZnPP都表现出上级其亲本分子的体内药代动力学，特别是在肿瘤递送中，通过利用大分子性质的EPR效应，从而显示出显着的抗肿瘤作用，表明这种抗癌治疗剂的临床应用潜力。此外，众所周知，许多抗氧化酶（如过氧化氢酶、超氧化物歧化酶）在体内大多数实体瘤中均下调。相反，HO-1被高度上调，并且它在抗氧化中起着非常重要的作用，因为HO-1产生胆绿素，胆绿素被转化为胆红素，表现出非常有效的抗氧化作用，因此在肿瘤中具有抗凋亡作用。因此，通过ZnPP抑制这种HO-1依赖性抗氧化剂（胆红素）形成，并通过增强ROS的产生，这种氧化疗法有望为未来的抗癌疗法提供一种强有力的治疗方式。
Reactive oxygen species (ROS), such as superoxide anion radicals (O-2(center dot-)) and hydrogen peroxide (H2O2) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS perse (e.g. H2O2) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O-2(center dot-) or H2O2-generating enzymes, xanthine oxiclase (XO) and D-amino acid oxiclase (DAO) (PEG-DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG-ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA-ZnPP, are prepared, which are potent inhibitors of heme oxygenase-1 (HO-1). HO-1 is a major antioxiclative enzyme of tumors, that is different in mechanism of catalase or superoxide dismutase (SOD). Consequently, both PEG-enzymes and PEG-ZnPP exhibited superior in vivo pharmacokinetics than their parental molecules, particularly in tumor delivery by taking advantage of the EPR effect of macromolecular nature, and thus showed remarkable antitumor effects suggesting the potentials of this anticancer therapeutic for clinical application. Furthermore, it has been well known that many antioxiclative enzymes such as catalase, SOD are down-regulated in most solid tumors in vivo. On the contrary, HO-1 is highly upregulated and it plays a very important role of antioxiclation, because HO-1 generates biliverdin, which being converted to bilirubin exhibits a very potent antioxidative effect, and hence antiapoptosis in tumors. Thus this oxidation therapy, by inhibiting this HO-1 dependent antioxidant (bilirubin) formation by ZnPP, and by enhancing ROS generation, is expected to offer a powerful therapeutic modality for future anticancer therapy.