Fang Jun, Sawa Tomohiro, Akaike Takaaki, Greish Khaled, Maeda Hiroshi
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Int J Cancer. 2004 Mar;109(1):1-8. doi: 10.1002/ijc.11644.
Heme oxygenase-1 (HO-1), an inducible enzyme that catalyzes oxidative degradation of heme to form biliverdin, carbon monoxide and free iron, may protect tumor cells against oxidative stress, thus contributing to rapid tumor growth in vivo. Here, we discuss whether pegylated zinc protoporphyrin (PEG-ZnPP), a potent HO inhibitor, modulates the chemotherapeutic response of tumor cells to treatment that generates reactive oxygen species (ROS). PEG-ZnPP is a water-soluble HO inhibitor that accumulates in tumor tissues after intravenous administration. Cytotoxicity of antitumor agents in vitro was determined by means of MTT and annexin V assays using human colon carcinoma SW480 cells. Mice bearing sarcoma 180 tumors were used as an in vivo model. Pegylated D-amino acid oxidase (PEG-DAO), which behaves as an oxidative chemotherapeutic agent by generating toxic oxidants at tumor tissues, was administered with its substrate D-proline to mice with or without PEG-ZnPP pretreatment. PEG-ZnPP-treated SW480 cells became vulnerable to insults caused by various cytotoxic agents; the 50% lethal doses were reduced by 25%, 39%, 83%, and 61% for hydrogen peroxide, t-butyl hydroperoxide, camptothecin and doxorubicin, respectively. Cells treated with PEG-ZnPP plus cytotoxic oxidants exhibited marked production of intracellular ROS, which paralleled the incidence of apoptosis. PEG-ZnPP pretreatment significantly reduced tumor growth in mice receiving PEG-DAO/D-proline compared to no PEG-ZnPP pretreatment. These findings suggest that HO-1 may become an attractive target for chemotherapeutic intervention. Further study of the effect of PEG-ZnPP plus conventional anticancer drugs that generate ROS, such as cisplatin, camptothecin, doxorubicin, mitomycin C and etoposide, is warranted.
血红素加氧酶-1（HO-1）是一种可诱导的酶，它催化血红素的氧化降解以形成胆绿素、一氧化碳和游离铁，可能保护肿瘤细胞免受氧化应激，从而促进体内肿瘤的快速生长。在此，我们探讨聚乙二醇化锌原卟啉（PEG-ZnPP），一种有效的HO抑制剂，是否能调节肿瘤细胞对产生活性氧（ROS）的治疗的化疗反应。PEG-ZnPP是一种水溶性HO抑制剂，静脉给药后可在肿瘤组织中蓄积。使用人结肠癌SW480细胞，通过MTT和膜联蛋白V测定法测定体外抗肿瘤药物的细胞毒性。携带肉瘤180肿瘤的小鼠用作体内模型。聚乙二醇化D-氨基酸氧化酶（PEG-DAO）通过在肿瘤组织中产生有毒氧化剂而作为一种氧化化疗药物，在有或没有PEG-ZnPP预处理的情况下与底物D-脯氨酸一起给予小鼠。经PEG-ZnPP处理的SW480细胞变得容易受到各种细胞毒性药物引起的损伤；过氧化氢、叔丁基过氧化氢、喜树碱和阿霉素的50%致死剂量分别降低了25%、39%、83%和61%。用PEG-ZnPP加细胞毒性氧化剂处理的细胞表现出细胞内ROS的显著产生，这与细胞凋亡的发生率平行。与未进行PEG-ZnPP预处理相比，PEG-ZnPP预处理显著降低了接受PEG-DAO/D-脯氨酸治疗的小鼠的肿瘤生长。这些发现表明HO-（此处原文有误，应为HO-1）可能成为化疗干预的一个有吸引力的靶点。有必要进一步研究PEG-ZnPP加常规产生ROS的抗癌药物（如顺铂、喜树碱、阿霉素、丝裂霉素C和依托泊苷）的效果。
