Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma

I. Mohiuddin, X. Cao, B. Fang, M. Nishizaki, W. R. Smythe

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The ratio of pro-apoptotic (PAP) and anti-apoptotic (AAP) bcl-2 proteins is important in apoptosis regulation. We sought to determine if inhibition of the AAP bcl-xl by sodium butyrate (SB) would augment apoptotic cellular death in mesothelioma when combined with adenoviral pro-apoptotic gene therapy (PAGT) by simultaneously increasing PAP and decreasing AAP in these cells. Human mesothelioma cell lines were exposed to AdBax, AdBak, Adp53, and SB alone as well as all vectors combined with SB at varying doses and time points. Cell death was assessed, and apoptosis evaluated by morphology and FACS. Isobologram analysis evaluated additive or synergistic effect. Cellular death and apoptosis were augmented by PAGT/SB combinations compared to monotherapy. Following AdBax/SB and AdBak/SB, a decrease of the AAP bcl-xl was noted in combination with increases in PAP bax and bak. By isobologram analysis, additive or synergistic cell killing was noted with both combinations. SB treatment did not significantly augment cell killing or apoptosis in combination with Adp53. PAGT/SB was more effective than monotherapy in induction of apoptotic cell death. Synergy may be due to the ability of SB to decrease bcl-xl with marked increases in PAP engendered by PAGT. Combination therapy with agents that down-regulate AAP in addition to PAGT may prove useful clinically.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalCancer Gene Therapy
Volume8
Issue number8
DOIs
Publication statusPublished - Sep 6 2001
Externally publishedYes

Keywords

  • Bak
  • Bax
  • Gene therapy
  • Mesothelioma
  • Sodium butyrate
  • bcl-2
  • bcl-xl
  • p53

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma'. Together they form a unique fingerprint.

  • Cite this