Cyclin-dependent kinase inhibitor, flavopiridol, induces apoptosis and inhibits tumor growth in drug-resistant Osteosarcoma and Ewing's family tumor cells

Yan Li, Kazuhiro Tanaka, Xu Li, Takamitsu Okada, Tomoyuki Nakamura, Minoru Takasaki, Shunsaku Yamamoto, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto

研究成果: Contribution to journalArticle査読

25 被引用数 (Scopus)

抄録

Multimodal therapies play important roles in the treatment of osteosarcoma (OS) and Ewing's family of tumors (EFTs), two most frequent malignant bone tumors. Although the clinical outcome of primary OS and EFTs is greatly improved, the relapsed cases often are associated with multidrug resistance of the tumors and the prognosis of these patients is still poor. Flavopiridol, a pan cyclin-dependent kinase (CDK) inhibitor is a novel antitumor agent that can induce cell cycle arrest and apoptosis in many cancer cells. However, there have been no studies about the effects of flavopiridol on drug-resistant OS and EFTs. Here, we demonstrated that flavopiridol induced the cleavage of poly-ADP-ribose polymerase (PARP) in a time and dose dependent manner in adriamycin-resistant OS and EFTs cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) as effectively as in their parental cells. Our data also snowed that flavopiridol caused the release of mitochondrial cytochrome c and the activation of caspase-9, caspase-8 and caspase-3, with an increase ratio of the proapoptotic protein level (Bax) to the antiapoptotic protein level (Bcl-2 and Bcl-XL), while apoptosis was inhibited by pan caspase inhibitor (Z-VAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK), not by caspase-8 inhibitor (Z-IETD-FMK). The treatment with flavopiridol further inhibited the tumor growth in mouse models of the drug-resistant OS and EFTs. These results suggest that flavopiridol might be promising in clinical therapy for the relapsed OS and EFTs.

本文言語英語
ページ(範囲)1212-1218
ページ数7
ジャーナルInternational Journal of Cancer
121
6
DOI
出版ステータス出版済み - 9 15 2007

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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