Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells

Cancer Chemother Pharmacol. 2002 Jul;50(1):46-52. doi: 10.1007/s00280-002-0465-z. Epub 2002 May 9.


Purpose: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family that preferentially kills tumor cells. In this study, we sought to determine whether chemotherapeutic agents augment TRAIL-induced cytotoxicity in human prostate cancer cells, and whether this sensitivity can be blocked by overexpression of bcl-2.

Methods: Prostate cancer cells, PC3 and LNCaP, were treated with TRAIL alone, drug alone or a combination of both for 24 h. Cytotoxicity was determined by DNA fragmentation and clonogenic survival assay.

Results: Treatment with the conventional chemotherapeutic agents cisplatin (2 and 5 microg/ml), etoposide (10 microM and 20 microM) and doxorubicin (30 and 60 n M) dramatically augmented TRAIL-induced apoptosis in LNCaP and PC3 cells. TRAIL-induced apoptosis was partially abrogated by overexpression of bcl-2 in these two cell lines when it was used in combination with the above agents. Similar results were obtained using clonogenic survival assays where bcl-2 overexpression was also found to marginally protect against TRAIL- and chemotherapy-induced cell killing.

Conclusions: This study demonstrates that combination treatment of prostate cancer cells with TRAIL and chemotherapeutic agents overcomes their resistance by triggering caspase activation. This greater than additive effect of cotreatment with TRAIL and chemotherapy may provide the basis for a new therapeutic approach to induce apoptosis in otherwise resistant cancer cells.

Publication types

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

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Combined Modality Therapy
  • Doxorubicin / pharmacology
  • Drug Synergism
  • Etoposide / pharmacology
  • Humans
  • Male
  • Membrane Glycoproteins / pharmacology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Stem Cell Assay


  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Etoposide
  • Doxorubicin
  • Caspases
  • Cisplatin