Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Cancer Gene Ther. 2002 Feb;9(2):164-72. doi: 10.1038/sj.cgt.7700420.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to induce apoptosis in malignant cells without harming normal cells. To determine the antitumor potential of TRAIL against prostate cells, we undertook a comprehensive study that included eight prostate cancer cells lines (CWR22Rv1, Du145, DuPro, JCA-1, LNCaP, PC-3, PPC-1, and TsuPr1) and primary cultures of normal prostate epithelial cells (PrEC). Cells were tested for susceptibility to soluble TRAIL in the presence or absence of the chemotherapeutic agent doxorubicin. TRAIL was also delivered by an adenoviral vector. Our results reveal that Du145, DuPro, LNCap, TsuPr1, and PrEC were resistant to 100 ng/mL TRAIL. JCA-1 and PPC-1 were slightly sensitive (20% killing) and PC-3 and CWR22Rv1 exhibited the highest sensitivity to TRAIL (30% and 50% killing, respectively). The combination of 10 ng/mL TRAIL with doxorubicin resulted in 60-80% cytotoxicity in seven of eight prostate cancer cells. TRAIL-mediated apoptosis involved cleavage of Bid, caspase-3, and PARP, and required caspase-8 and -9 activity. Full-length TRAIL delivered by an adenoviral vector (AdTRAIL-IRES-GFP) killed prostate cancer cell lines and PrEC without requisite doxorubicin cotreatment. Therefore, expression of the transgene from a tissue-specific promotor would make gene therapy with AdTRAIL-IRES-GFP a possibility.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cytochrome c Group / metabolism
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Genetic Vectors
  • Humans
  • Ligands
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Ligands
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Doxorubicin
  • Poly(ADP-ribose) Polymerases
  • Caspases