Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis

A. Zisman, C. P. Ng, A. J. Pantuck, B. Bonavida, A. S. Belldegrun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The cytotoxic efficacy and kinetics involved in sensitization of Apo2L/TRAIL-resistant, androgen-independent prostate cancer cells to Apo2L/TRAIL or tumor necrosis factor-α or Fas ligand-mediated apoptosis were tested using subclinical concentrations of actinomycin D, paclitaxel, cisplatinum, gemcitabine, and radiation in CL-1, LNCaP, DU-145, and PC3 prostate cancer cell lines. CL-1 cells expressed all four Apo2L/TRAIL receptors and were resistant to Apo2L/TRAIL-mediated apoptosis (1-5,000 ng/mL) and to the sensitizers when given alone. Pretreatment with actinomycin D followed by Apo2L/TRAIL or tumor necrosis factor-α or anti-Fas CH-11 monoclonal antibody, but not in the reverse order, induced apoptosis in all cell lines. Synergistic sensitization in CL-1 cells was shown also with gemcitabine but not with cisplatinum, VP-16, paclitaxel, or radiation. Incubating the Apo2L/TRAIL-resistant CL-1, LNCaP, DU-145, and PC3 cell lines with 100 ng/mL actinomycin D for 4 hours followed by Apo2L/TRAIL for 24 hours resulted in 45.4 ± 10.3%, 58.8 ± 3.6%, 53.4 ± 1.4%, and 84.2 ± 8.4% apoptosis, respectively. Prolonging the sensitization time to 24 hours followed by 20 hours of incubation with Apo2L/TRAIL further enhanced the killing activity against CL-1 cells to 89 ± 1% (Δ = 60%, synergistic ratio = 3.1). This killing has a biphasic pattern that was contributed to by apoptosis (83%) and necrosis (17%) at 10 hours (peak) and 40% and 60%, respectively, at 20 hours. These results suggest that prostate cancer cells' resistance to Apo2L/TRAIL-mediated apoptosis can be reversed and synergy is achieved by sensitization of tumor cells with subclinical concentrations of actinomycin D or gemcitabine and may be useful clinically for the treatment of metastatic hormone- and drug-refractory prostate cancer.

Original languageEnglish
Pages (from-to)459-471
Number of pages13
JournalJournal of Immunotherapy
Volume24
Issue number6
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Androgen independent
  • Apo2L/TRAIL
  • Chemotherapy
  • Combination therapy
  • Prostate cancer
  • Synergy

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