Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin

Jun Fang, Tomohiro Sawa, Takaaki Akaike, Khaled Greish, Hiroshi Maeda

Research output: Contribution to journalArticlepeer-review

145 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalInternational Journal of Cancer
Volume109
Issue number1
DOIs
Publication statusPublished - 2004 Mar 10

Keywords

  • D-amino acid oxidase
  • Heme oxygenase-1
  • Macromolecular therapeutics
  • Tumor targeting/EPR effect
  • Zinc protoporphyrin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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