Celecoxib disrupts the canonical apoptotic network in HTLV-I cells through activation of Bax and inhibition of PKB/Akt

Apoptosis. 2008 Jan;13(1):33-40. doi: 10.1007/s10495-007-0148-7.

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease of very poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). Treatment of patients with ATLL using conventional chemotherapy has limited benefit because HTLV-I cells are refractory to most apoptosis-inducing agents. In this study, we report that Celecoxib induces cell death via the intrinsic mitochondrial pathway in HTLV-I transformed leukemia cells. Treatment with Celecoxib was associated with activation of Bax, decreased expression of Mcl-1, loss of the mitochondrial membrane potential and caspase-9-dependent apoptosis. These effects were independent from Bcl-2 and Bcl-xL. We also found that Celecoxib inhibited the Akt/GSK3 beta survival pathway in HTLV-I cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects*
  • Celecoxib
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclooxygenase Inhibitors / pharmacology*
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology*
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrazoles / pharmacology*
  • Sulfonamides / pharmacology*
  • bcl-2-Associated X Protein / metabolism*
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • Cyclooxygenase Inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazoles
  • Sulfonamides
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Proto-Oncogene Proteins c-akt
  • Celecoxib