In vitro establishment of cis-diammine-dichloroplatinum(II) resistant lung cancer cell line and modulation of apoptotic gene expression as a mechanism of resistant phenotype.
After exposure of H460 cells to an increasing concentrations of cis-diammine-dichloroplatinum(II) (cisplatin, CDDP) for 6 months, cisplatin resistant cells were isolated (H460/CIS). The biologic behaviors of H460 and H460/CIS cells were tested using animal experiments. Only the resistant cells developed lung metastases despite cisplatin treatment. The characteristics of H460/CIS cells are as follows, MTT analyses revealed that H460/CIS cells were markedly resistant to cisplatin compared with their parental cells. Also, H460/CIS cells exhibited cross-resistance to DNA damaging agents such as doxorubicin (DXR) and etoposide. Cisplatin treatment dramatically increased p53 expression in parental cells but not in H460/CIS cells which expressed basal levels of p53. Without cisplatin treatment, Bcl-2 and Bax were expressed in H460/CIS cells, but not in parental cell. Our data suggested that p53, Bax and Bcl-2 were up-regulated in H460/CIS cells. These changes could explain some of the mechanisms of cisplatin resistance. Thus, H460/CIS could be useful to investigate the mechanisms of drug resistance to cisplatin including apoptotic gene expressions conferring drug resistance, thereby making progress in the treatment of cisplatin-resistant tumor cells.
Yoon
S S
SS
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Ahn
K S
KS
Kim
S H
SH
Shim
Y M
YM
Kim
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D005562:Formazans; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013778:Tetrazolium Salts; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005562:Formazans; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C079782:MTT formazan; D002945:Cisplatin