Topoisomerase inhibitor-induced apoptosis accompanied by down-regulation of Bcl-2 in human lung cancer cells

Anticancer Res. Nov-Dec 2002;22(6C):4029-37.

Abstract

Background: Anticancer drug-induced apoptosis is one of the important mechanisms in the effectiveness of chemotherapy. In this study, we investigated apoptosis induced by topoisomerase inhibitors and its relationship with chemosensitivity, the expression of Bcl-2 family proteins and p53 status in human lung cancer cells.

Materials and methods: A total of six human lung cancer cell lines, i.e., two small cell lung cancer (SCLC) and four non-small cell lung cancer (NSCLC) cell lines, were used. For induction of apoptosis, these cell lines were treated with SN-38 (DNA topoisomerase I inhibitor) or etoposide (DNA topoisomerase II inhibitor). Drug sensitivity was determined using a microculture tetrazolium assay. The rates of apoptosis and alterations of Bcl-2 and Bax expression were analyzed by flow cytometry.

Results: Apoptotic cells increased in a time-dependent manner after exposure to topoisomerase inhibitors. Induction of apoptosis was accompanied by the down-regulation of Bcl-2 expression, but there was little alteration of Bax expression. These events were significantly more extensive in SCLC cell lines, which are more sensitive to topoisomerase inhibitors, than in NSCLC cell lines, which are more resistant to these inhibitors. However, neither induction of apoptosis nor chemosensitivity correlated with p53 status in the lung cancer cell lines studied.

Conclusion: The more extensive induction of apoptosis with Bcl-2 down-regulation in SCLC than in NSCLC might explain, at least in part, the higher clinical sensitivity to topoisomerase inhibitors in the former disease.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / enzymology
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology*
  • Flow Cytometry
  • Humans
  • Irinotecan
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / biosynthesis
  • bcl-2-Associated X Protein

Substances

  • Antineoplastic Agents, Phytogenic
  • BAX protein, human
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Etoposide
  • Irinotecan
  • Camptothecin