Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors

Biochem Pharmacol. 2010 Dec 1;80(11):1650-61. doi: 10.1016/j.bcp.2010.08.018. Epub 2010 Sep 8.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising anticancer agent but cutaneous T lymphoma cells (CTCL) are less sensitive to TRAIL-induced apoptosis. Here, we report that pentoxifylline (PTX), a phosphodiesterase inhibitor, augments TRAIL-mediated apoptosis in HuT-78 and MyLa cells through modulating extrinsic death receptors and intrinsic mitochondria dependent pathways. Our results clearly show that PTX augments TRAIL-mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone cannot activate caspase-8. This is followed by cytochrome c release and subsequent, activation of caspase-9 and caspase-3 and cleavage of poly (ADP ribose) polymerase (PARP). Combined treatment downregulates the expression of various antiapoptotic proteins including c-FLIP, Bcl-xl, cIAP-1, cIAP-2 and XIAP. PTX induces the expression of death receptors DR4 and DR5 on cell surface of both the cell types where c-Jun NH2-terminal kinase (JNK) pathway plays an important role. Moreover, combined silencing of DR4 and DR5 by small interfering RNA abrogates the ability of PTX to induce TRAIL-mediated apoptosis. Thus, this is the first demonstration that PTX can potentiate TRAIL-mediated apoptosis through downregulation of cell survival gene products and upregulation of death receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Pharmaceutic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / biosynthesis*
  • Apoptosis Regulatory Proteins / physiology
  • Cell Line, Tumor
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Lymphoma, T-Cell, Cutaneous / metabolism
  • Lymphoma, T-Cell, Cutaneous / pathology*
  • Pentoxifylline / pharmacology*
  • Receptors, Death Domain / biosynthesis*
  • Receptors, Death Domain / physiology
  • TNF-Related Apoptosis-Inducing Ligand / physiology*

Substances

  • Adjuvants, Pharmaceutic
  • Apoptosis Regulatory Proteins
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Pentoxifylline