Ectopic expression of herpes simplex virus-thymidine kinase gene in human non-small cell lung cancer cells conferred caspase-activated apoptosis sensitized by ganciclovir

Chien Chih Chiu, Yuan Lin Kang, Tsung Hsiang Yang, Chih Hsin Huang, Kang Fang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Human non-small cell lung cancer (NSCLC) cells were transfected with recombinant prodrug herpes simplex virus type I thymidine kinase (HSV-tk) cDNA, and the selected clones underwent apoptosis in response to induction by antiviral ganciclovir (GCV). The efficiency of GCV-induced growth inhibition and the extent of the bystander effect were associated with the expression level of HSV-TK in stable transfectants. Development in the HSV-tk/GCV system toward cell death was initiated with cell-cycle accumulation at S and G2/M phases, immediately followed by the appearance of sub-G0/G1 cells after drug exposure. To investigate the regulation of cell-cycle modulators during drug treatment, we analyzed release of the apoptosis initiator cytochrome c and activation of the downstream effectors caspase-9, caspase-3 and poly(ADP-ribose)polymerase 16 hr after GCV sensitization, followed by transient escalation of tumor-suppressor p53 and cell-cycle modulators cyclin A and B1 before committing to programmed cell death. Furthermore, tumor regression was proportional to the degree of ectopic expression of the transferred HSV-tk gene. Our results demonstrate that the HSV-tk/GCV system effectively inhibits the proliferation of NSCLC cells in vitro and in vivo through potent induction of apoptosis, thus providing a rationale for further development.

Original languageEnglish
Pages (from-to)328-333
Number of pages6
JournalInternational Journal of Cancer
Volume102
Issue number4
DOIs
Publication statusPublished - 2002 Dec 1

Keywords

  • Apoptosis
  • Cell cycle
  • Herpes simplex virus-thymidine kinase
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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