The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis

  • Authors:
    • Kazumi Miyashita
    • Katsuya Shiraki
    • Hiroyuki Fuke
    • Tomoko Inoue
    • Yutaka Yamanaka
    • Yumi Yamaguchi
    • Norihiko Yamamoto
    • Keiichi Ito
    • Kazushi Sugimoto
    • Takeshi Nakano
  • View Affiliations

  • Published online on: August 1, 2006     https://doi.org/10.3892/ijmm.18.2.249
  • Pages: 249-256
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Abstract

Flavopiridol was one of the first cyclin-dependent kinase inhibitors demonstrated to have an antitumor effect in several cancer types. Here, we investigated the effects of flavopiridol on TNF-related apoptosis-inducing ligand (TRAIL) in the human hepatocellular carcinoma (HCC) cell lines HLE and HepG2, and evaluated the role of flavopiridol in apoptosis. To better understand the mechanism of increased TRAIL sensitivity in HCC cells, we determined the effect of flavopiridol on cell surface expression of TRAIL and TRAIL receptors using flow cytometry analysis. The levels of survivin, FLIP, Bcl-xL and X-chromosome-linked IAP (XIAP) in treated and untreated cells was also determined. Flavopiridol decreased cell viability in a dose-dependent manner in the two HCC cell lines tested. The pan-caspase inhibitor z-VAD-FMK did not inhibit the effect. However, subtoxic levels of flavopiridol dramatically enhanced TRAIL-induced apoptosis in both cells. Flavopiridol up-regulated TRAIL, TRAIL-R1 and TRAIL-R2 in both cell lines. In addition, flavopiridol down-regulated expression of survivin in both cell lines, and expression of FLIP and Bcl-xL were down-regulated in HLE cells. In summary, flavopiridol augmented TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of survivin, FLIP and Bcl-xL. Thus, combining flavopiridol with a TRAIL agonist may prove to be an effective new strategy for treatment of HCC.

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August 2006
Volume 18 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Miyashita K, Shiraki K, Fuke H, Inoue T, Yamanaka Y, Yamaguchi Y, Yamamoto N, Ito K, Sugimoto K, Nakano T, Nakano T, et al: The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis. Int J Mol Med 18: 249-256, 2006
APA
Miyashita, K., Shiraki, K., Fuke, H., Inoue, T., Yamanaka, Y., Yamaguchi, Y. ... Nakano, T. (2006). The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis. International Journal of Molecular Medicine, 18, 249-256. https://doi.org/10.3892/ijmm.18.2.249
MLA
Miyashita, K., Shiraki, K., Fuke, H., Inoue, T., Yamanaka, Y., Yamaguchi, Y., Yamamoto, N., Ito, K., Sugimoto, K., Nakano, T."The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis". International Journal of Molecular Medicine 18.2 (2006): 249-256.
Chicago
Miyashita, K., Shiraki, K., Fuke, H., Inoue, T., Yamanaka, Y., Yamaguchi, Y., Yamamoto, N., Ito, K., Sugimoto, K., Nakano, T."The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis". International Journal of Molecular Medicine 18, no. 2 (2006): 249-256. https://doi.org/10.3892/ijmm.18.2.249