Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: Involvement of both death receptor and mitochondrial pathways

  • Authors:
    • Sharmila Shankar
    • Thiyam R. Singh
    • Tamer E. Fandy
    • Thitidaj Luetrakul
    • Douglas D. Ross
    • Rakesh K. Srivastava
  • View Affiliations

  • Published online on: December 1, 2005     https://doi.org/10.3892/ijmm.16.6.1125
  • Pages: 1125-1138
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Abstract

In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.

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December 2005
Volume 16 Issue 6

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

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APA
Shankar, S., Singh, T.R., Fandy, T.E., Luetrakul, T., Ross, D.D., & Srivastava, R.K. (2005). Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: Involvement of both death receptor and mitochondrial pathways. International Journal of Molecular Medicine, 16, 1125-1138. https://doi.org/10.3892/ijmm.16.6.1125
MLA
Shankar, S., Singh, T. R., Fandy, T. E., Luetrakul, T., Ross, D. D., Srivastava, R. K."Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: Involvement of both death receptor and mitochondrial pathways". International Journal of Molecular Medicine 16.6 (2005): 1125-1138.
Chicago
Shankar, S., Singh, T. R., Fandy, T. E., Luetrakul, T., Ross, D. D., Srivastava, R. K."Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: Involvement of both death receptor and mitochondrial pathways". International Journal of Molecular Medicine 16, no. 6 (2005): 1125-1138. https://doi.org/10.3892/ijmm.16.6.1125