Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells

Mol Cancer. 2008 Jun 30;7:60. doi: 10.1186/1476-4598-7-60.

Abstract

Background: Drug resistance is a major concern in cancer therapy. Here, we investigate the clinical potential of the second mitochondria-derived activator of caspase (Smac/DIABLO) in enhancing the apoptosis-inducing potential of commonly used anticancer drugs (paclitaxel, doxorubicin, etoposide, tamoxifen), irradiation and TRAIL in breast carcinoma.

Methods: Breast cancer cells were overexpressed with Smac/DIABLO gene (full-length or Delta55 Smac/DIABLO) or treated with Smac/DIABLO peptide to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant cells. Cell viability and apoptosis were measured by XTT assay and DAPI staining, respectively. Protein-protein interaction was determined by immunoprecipitation followed by the Western blot analysis.

Results: Overexpression of Smac/DIABLO gene (full-length or Delta55 Smac/DIABLO) or treatment with Smac/DIABLO peptide enhances apoptosis induced by paclitaxel, doxorubicin, etoposide, tamoxifen, and irradiation in breast cancer cells. Overexpression of Smac/DIABLO resulted in an increased interaction of Smac/DIABLO with IAPs, which correlated with an increase in caspase-3 activity and apoptosis. Furthermore, Smac/DIABLO sensitized TRAIL-resistant breast cancer cell lines to undergo apoptosis through caspase-3 activation. These data suggest that apoptotic events down-stream of mitochondria were intact in TRAIL-resistant cells since ectopic expression of Smac/DIABLO or pretreatment of cells with Smac/DIABLO peptide completely restored TRAIL sensitivity.

Conclusion: The ability of Smac/DIABLO agonists to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant tumor cells suggests that Smac/DIABLO may induce fundamental alterations in cell signaling pathways. Thus, Smac/DIABLO agonists can be used as promising new candidates for cancer treatment by potentiating cytotoxic therapies.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Collagen Type XI / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / radiation effects
  • Enzyme Activation / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Photosensitizing Agents / pharmacology*
  • Protein Binding
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*

Substances

  • Antineoplastic Agents
  • Collagen Type XI
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Photosensitizing Agents
  • TNF-Related Apoptosis-Inducing Ligand
  • Caspase 3