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Flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL

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Abstract

Purpose

Flavopiridol is known to modulate the transcription of genes. We investigated the effect of flavopiridol pretreatment on TRAIL cytotoxicity and on the expression of FLIPL in different TRAIL-resistant cell lines, because FLIP expression is known to confer TRAIL-resistance.

Methods

Apoptosis was assessed by PI staining and protein expression by Western blotting. RT-PCR was used for mRNA quantitation. siRNA gene silencing was used to knock down FLIPL.

Results

Flavopiridol pretreatment synergized TRAIL-induced apoptosis in human myeloma and breast cancer cells. Flavopiridol treatment repressed the transcription of FLIPL and downregulated its expression in both myeloma and breast cancer cells. Silencing of FLIPL gene by siRNA sensitized myeloma cells to TRAIL. Flavopiridol treatment downregulated the expression of the proapoptotic members of the Bcl-2 family proteins (Bak, Bax and PUMA-α). The expression of the antiapototic Bcl-2 members (Bcl-2 and Bcl-XL) was not altered by flavopiridol treatment in myeloma cells.

Conclusion

Our data indicate that flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL and this synergistic effect is Bcl-2 family independent.

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Author notes

  1. Rakesh K. Srivastava

    Present address: Center for Biomedical Research, University of Texas Health Center, Tyler, TX, 75708, USA

Authors and Affiliations

  1. School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201, USA

    Tamer E. Fandy & Rakesh K. Srivastava

  2. Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Douglas D. Ross & Rakesh K. Srivastava

  3. Baltimore VA Medical Center, Baltimore, MD, 21201, USA

    Douglas D. Ross

  4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans St, CRB 233, Baltimore, MD, 21231, USA

    Tamer E. Fandy & Steven D. Gore

Authors
  1. Tamer E. Fandy
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  2. Douglas D. Ross
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  3. Steven D. Gore
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  4. Rakesh K. Srivastava
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Correspondence to Tamer E. Fandy.

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Fandy, T.E., Ross, D.D., Gore, S.D. et al. Flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL . Cancer Chemother Pharmacol 60, 313–319 (2007). https://doi.org/10.1007/s00280-006-0381-8

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  • DOI: https://doi.org/10.1007/s00280-006-0381-8

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