Cell death induced by taxanes in breast cancer cells: cytochrome C is released in resistant but not in sensitive cells

Anticancer Res. 2005 Nov-Dec;25(6B):4215-24.

Abstract

Background: The aim of the study was to contribute to our understanding of the mechanisms responsible for the resistance of breast cancer cells to taxanes.

Materials and methods: Cell cycle characteristics, DNA fragmentation, p53 and p21(WAF1/CIP1) expression, caspase-3 and caspase-9 activity, cytochrome c release from mitochondria during cell death induction by the taxanes paclitaxel and docetaxel in highly-sensitive MDA-MB-435 and highly-resistant NCI-ADR-RES human breast cancer cells were compared.

Results: Approximately 300-fold higher concentrations of the taxanes were required to induce death in resistant NCI-ADR-RES cells than in sensitive MDA-MB-435 cells. Cell death induced by the taxanes in both sensitive and resistant cells was preceded by the accumulation of cells in the G2/M-phase. Neither cell type produced any DNA fragmentation (DNA ladder) typical of regular apoptosis. The p53 and the p21(WAF1/CIP1) levels did not change in sensitive or in resistant cells during cell death induction by the taxanes. The activity of the executioner caspase-3 increased significantly (2 to 2.5-fold) and, similarly, the activity of caspase-9 increased significantly (2 to 3.5-fold) in both cell types. However, cytochrome c was found to be released from mitochondria into the cytosol only in the resistant NCI-ADR-RES cells, but not in the sensitive MDA-MB-435 cells.

Conclusion: The death induced by the taxanes in the studied breast cancer cells can be characterized as an apoptosis-like death, including caspase-3 and caspase-9 activation but not oligonucleosomal DNA fragmentation. However, the mechanisms of death induction by the taxanes in sensitive MDA-MB-435 cells and resistant NCI-ADR-RES cells differ. Cytochrome c is released from the mitochondria in resistant but not in sensitive cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cytochromes c / metabolism*
  • DNA Fragmentation / drug effects
  • Docetaxel
  • Drug Resistance, Neoplasm
  • Humans
  • Paclitaxel / pharmacology*
  • Taxoids / pharmacology*
  • Tumor Suppressor Protein p53 / biosynthesis

Substances

  • Antineoplastic Agents, Phytogenic
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53 protein, human
  • Taxoids
  • Tumor Suppressor Protein p53
  • Docetaxel
  • Cytochromes c
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • Paclitaxel