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Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 3, pp 313–319 | Cite as

Flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL

  • Tamer E. Fandy
  • Douglas D. Ross
  • Steven D. Gore
  • Rakesh K. Srivastava
Original Article

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.

Keywords

Flavopiridol FLIP TRAIL Bcl-2 family Apoptosis 

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Tamer E. Fandy
    • 1
    • 4
  • Douglas D. Ross
    • 2
    • 3
  • Steven D. Gore
    • 4
  • Rakesh K. Srivastava
    • 1
    • 2
    • 5
  1. 1.School of Pharmacy, Department of Pharmaceutical SciencesUniversity of MarylandBaltimoreUSA
  2. 2.Greenebaum Cancer Center, School of MedicineUniversity of MarylandBaltimoreUSA
  3. 3.Baltimore VA Medical CenterBaltimoreUSA
  4. 4.Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA
  5. 5.Center for Biomedical ResearchUniversity of Texas Health CenterTylerUSA

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