title: Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin.
abstract: 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.
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001835:Body Weight; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D008665:Metalloporphyrins; D016877:Oxidants; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C476103:pegylated zinc protoporphyrin; D011092:Polyethylene Glycols; D016685:Mitomycin; D005047:Etoposide; D004317:Doxorubicin; D011392:Proline; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); C022616:thiazolyl blue; D002945:Cisplatin; D010100:Oxygen; D002166:Camptothecin