IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide

Atsushi Natsume; Dai Ishii; Toshihiko Wakabayashi; Takaya Tsuno; Hisashi Hatano; Masaaki Mizuno; Jun Yoshida

doi:10.1158/0008-5472.CAN-05-0036

IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide

Cancer Res. 2005 Sep 1;65(17):7573-9. doi: 10.1158/0008-5472.CAN-05-0036.

Authors

Atsushi Natsume¹, Dai Ishii, Toshihiko Wakabayashi, Takaya Tsuno, Hisashi Hatano, Masaaki Mizuno, Jun Yoshida

Affiliation

¹ Center for Genetic and Regenerative Medicine, Nagoya University Hospital, Japan. anatsume@med.nagoya-u.ac.jp

PMID: 16140920
DOI: 10.1158/0008-5472.CAN-05-0036

Abstract

Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.

MeSH terms

Antineoplastic Agents, Alkylating / administration & dosage
Antineoplastic Agents, Alkylating / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Line, Tumor
DNA Methylation
DNA Repair / genetics
Dacarbazine / administration & dosage
Dacarbazine / analogs & derivatives*
Dacarbazine / pharmacology
Down-Regulation / drug effects
Drug Resistance, Neoplasm
Drug Synergism
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Glioma / drug therapy*
Glioma / enzymology
Glioma / genetics*
Humans
Interferon-beta / administration & dosage
Interferon-beta / pharmacology*
O(6)-Methylguanine-DNA Methyltransferase / biosynthesis
O(6)-Methylguanine-DNA Methyltransferase / genetics*
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Temozolomide
Tumor Suppressor Protein p53 / physiology

Substances

Antineoplastic Agents, Alkylating
Tumor Suppressor Protein p53
Interferon-beta
Dacarbazine
O(6)-Methylguanine-DNA Methyltransferase
Temozolomide