Down-regulation of Bcl-2 is associated with cisplatin resistance in human small cell lung cancer H69 cells

Mol Cancer Ther. 2004 Mar;3(3):327-34.

Abstract

Overexpression of the anti-apoptotic protein Bcl-2 has been associated with several malignancies, including small cell lung cancer (SCLC). In the present study, we have investigated if Bcl-2 contributes to the emergence of cisplatin resistance in SCLC H69 cells. The ability of cisplatin to induce apoptosis was decreased in H69 cells that acquired resistance to cisplatin (H69/CP). The level of Bcl-2 was, however, substantially reduced in H69/CP cells compared to parental H69 cells. There was little change in Bcl-2 content in H69 cells that were resistant to etoposide (VP-16) or Taxol. Bcl-2 was constitutively phosphorylated at serine 70 in H69 cells but not in H69/CP cells and cisplatin had little effect on Bcl-2 phosphorylation. The level of procaspase-3 was elevated in H69/CP cells but the ability of cisplatin to induce mitochondrial depolarization, caspase-9 activation, and poly(ADP-ribose) polymerase (PARP) cleavage was compromised in H69/CP cells. The level of the anti-apoptotic protein Bcl-x(L) and the pro-apoptotic protein Bax was slightly reduced in H69/CP cells but the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins was not sufficient to explain cellular resistance to cisplatin. These results suggest that the acquisition of cisplatin resistance by H69 cells was not due to an increase in the level/phosphorylation status of the anti-apoptotic protein Bcl-2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetophenones / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis
  • Benzopyrans / pharmacology
  • Blotting, Western
  • Carcinoma, Small Cell
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Down-Regulation*
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Lung Neoplasms / pathology*
  • Membrane Potentials
  • Mitochondria / pathology
  • Paclitaxel / pharmacology
  • Phosphorylation
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors

Substances

  • Acetophenones
  • Antineoplastic Agents, Phytogenic
  • Benzopyrans
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Etoposide
  • rottlerin
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • Paclitaxel
  • Cisplatin