Enhanced nucleotide excision repair in cisplatin resistant human KB carcinoma cells.
We previously reported that enhanced active efflux of cisplatin and increased GSH level were observed in KCP-4 cells. In the present study, KCP-4 cells were found to be cross-resistant to ultraviolet (UV) compared with parental KB-3-1 cells. Enhanced nucleotide excision repair (NER) was verified by time-dependent repair of UV-induced DNA damage. In addition, the amount of platinum bound to DNA after exposure to cisplatin decreased in a time-dependent manner in KCP-4 cells and this was reversed by aphidicolin, a DNA polymerase inhibitor. In stationary phase cultures, aphidicolin increased the sensitivity of KCP-4 cells to cisplatin. The expression of xeroderma pigmentosum complementation group F (XPF), an endonuclease involved in NER, was upregulated in KCP-4 cells. In KCP-4 cells the expression of hMSH6, one of the mismatch repair (MMR) factors, was decreased compared to parental KB-3-1 and revertant KCP-4R cells. However, KCP-4 cells were cross-resistant to oxaliplatin, and microsatellite instability was not observed in them. These findings suggest that the enhanced NER activity for DNA damage caused by cisplatin may be involved in cisplatin resistance in KCP-4 cells.
Mukai
Motoi
M
Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
Kanzaki
Atsuko
A
Chen
Zhe-Sheng
ZS
Miyashita
Hitoshi
H
Sumizawa
Tomoyuki
T
Furukawa
Tatsuhiko
T
Haraguchi
Misako
M
Takebayashi
Yuji
Y
Takamatsu
Hideo
H
Akiyama
Shin-ichi
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D020137:Base Pair Mismatch / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000528:radiation effects*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004273:DNA, Neoplasm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D018895:Microsatellite Repeats; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014466:Ultraviolet Rays; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C094443:G-T mismatch-binding protein; D009944:Organoplatinum Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; C095888:xeroderma pigmentosum group F protein; D000077150:Oxaliplatin; D016590:Aphidicolin; D004257:DNA Polymerase II; C022616:thiazolyl blue; D002945:Cisplatin