Enhancement of drug-induced apoptosis by antisense oligodeoxynucleotides targeted against Mdm2 and p21(WAF1/CIP1)

Norihiro Sato, Kazuhiro Mizumoto, Naoki Maehara, Masahiro Kusumoto, Shoko Nishio, Taro Urashima, Takahiro Ogawa, Masao Tanaka

研究成果: Contribution to journalArticle査読

33 被引用数 (Scopus)

抄録

The p53 tumor suppressor gene plays an important role in DNA damage-induced apoptosis and, in general, inactivation of p53 contributes to poor response to chemotherapy. Apoptotic activity of p53 may be negatively modulated by expression of its downstream mediators, including Mdm2 and p21(WAF1/CIP1). Consequently, these cellular pathways also represent potential targets for cancer therapy. This study investigated the effect of antisense oligodeoxynucleotides (ODNs), targeted against Mdm2 and p21(WAF1/CIP1) on drug-mediated cell killing. Exposure of U2-OS osteosarcoma cells to DNA damaging agents, cisplatin or mitomycin C, caused upregulated expression of Mdm2 and p21(WAF1/CIP1). Transient transfection of cells with antisense ODNs to Mdm2 mRNA inhibited Mdm2 protein expression and markedly enhanced apoptotic cell death induced by these drugs. Moreover, when p21(WAF1/CIP1) expression was blocked by antisense transfection, drug-mediated cell killing was further accelerated. These results suggest that the enhanced expression of Mdm2 and p21(WAF1/CIP1) may inhibit p53-mediated apoptosis and render cells resistant to the effects of DNA damaging agents. Consequently, antisense ODNs targeted against Mdm2 and p21(WAF1/CIP1) could be employed in a potential therapeutic strategy sensitizing tumor cells to certain antineoplastic agents.

本文言語英語
ページ(範囲)837-842
ページ数6
ジャーナルAnticancer research
20
2 A
出版ステータス出版済み - 2000

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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