The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells

Tomoyuki Nakamura, Kazuhiro Tanaka, Tomoya Matsunobu, Takamitsu Okada, Fumihiko Nakatani, Riku Sakimura, Masuo Hanada, Yukihide Iwamoto

研究成果: Contribution to journalArticle査読

34 被引用数 (Scopus)

抄録

EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21waf1/cip1 and p27kip1 expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21waf1/cip1 and p27kip1 expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the overexpression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.

本文言語英語
ページ(範囲)803-811
ページ数9
ジャーナルInternational journal of oncology
31
4
DOI
出版ステータス出版済み - 10 2007

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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