title: Topoisomerase inhibitor-induced apoptosis accompanied by down-regulation of Bcl-2 in human lung cancer cells.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Oizumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Isobe
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ogura
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D000077146:Irinotecan; D002166:Camptothecin