Overcoming acquired resistance to TRAIL by chemotherapeutic agents and chain inhibitor I through distinct mechanisms

Hongbo Zhu, Lidong Zhang, Xuefeng Huang, John J. Davis, Dietmar A. Jacob, Fuminori Teraishi, Paul Chiao, Bingliang Fang

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

We recently found that repeated application of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or recombinant TRAIL proteins to TRAIL-susceptible cancer cells resulted in selection and expansion of TRAIL-resistant cells. Overcoming this acquired resistance to TRAIL is desirable for TRAIL-mediated cancer therapy. Here we demonstrate that several chemotherapeutic agents, including 5-fluorouracil (5-FU) and mitomycin, and calpain inhibitor I, an NFκB inhibitor, can overcome acquired resistance to TRAIL in DLD1 colon cancer cells. The combination of TRAIL (approved gene symbol TNFSF10) gene therapy and 5-FU enhanced tumor suppression in vivo in nude mice bearing subcutaneous tumors established from TRAIL-resistant colon cancer cells. Whereas treatment with the combination of TRAIL and 5-FU or mitomycin led to enhanced activation of caspase-3, the combination of TRAIL and calpain inhibitor I resulted in enhanced activation of both caspase-8 and caspase-3. Moreover, mitomycin, but not 5-FU or calpain inhibitor I, induced overexpression of the BAX gene, which was correlated with enhanced TRAIL-induced cell killing in TRAIL-resistant DLD1 cells. Together, these results suggest that acquired resistance to TRAIL can be overcome by different mechanisms and that combinations of TRAIL gene therapy and chemotherapy may be a useful approach for cancer treatment.

Original languageEnglish
Pages (from-to)666-673
Number of pages8
JournalMolecular Therapy
Volume9
Issue number5
DOIs
Publication statusPublished - May 2004
Externally publishedYes

Keywords

  • Combination therapy
  • Death receptor
  • Gene therapy
  • TRAIL

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Overcoming acquired resistance to TRAIL by chemotherapeutic agents and chain inhibitor I through distinct mechanisms'. Together they form a unique fingerprint.

  • Cite this