Isolation and characterization of arsenite-resistant human epidermoid carcinoma KB cells.
Arsenic trioxide (As2O3) has been used with success in the treatment of acute promyelocytic leukemia. However, resistance to arsenite agents reduces their efficacy. We have isolated arsenite-resistant human epidermoid carcinoma KB cells, termed KAS. KAS cells were resistant to sodium arsenite (22-fold) and showed a reduced accumulation of arsenite as a result of an active efflux mechanism. Further analysis indicated that resistance of KAS cells extended to other drugs including cisplatin (17-fold), antimony potassium tartrate (11-fold) and doxorubicin (27-fold). Although increased expression of multidrug resistance protein 1 (MRP1) in KAS cells was confirmed by quantitative RT-PCR and immunoblot analysis, specific inhibitors of MRP1 did not completely eliminate arsenite resistance. The level of glutathione (GSH) in KAS cells was 3-fold higher than that in KB-3-1 cells, and the inhibition of GSH synthesis by buthionine sulfoximine (BSO) considerably increased the cytotoxic effect of arsenite on KAS cells. A pyridine analog, 2-[4-(diphenylmethyl)-1-piperazinyl ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine-carboxylate P oxide (PAK-104P), partially reversed the arsenite resistance and increased the arsenite accumulation in KAS cells. We suggest that the increased level of GSH is involved in arsenite resistance and an as yet unidentified arsenite transporter is expressed in the arsenite-resistant KAS cells.
Department of Molecular Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Japan.
Tokushi
T
Tachiwada
Zhe-Sheng
ZS
Chen
Xiao-Fang
XF
Che
Mitsugu
M
Matsumoto
Misako
M
Haraguchi
Takenari
T
Gotanda
Tomoyuki
T
Sumizawa
Tatsuhiko
T
Furukawa
Kenryu
K
Nishiyama
Naohiko
N
Seki
Masatatsu
M
Yamamoto
Masayuki
M
Nakagawa
Shin-Ichi
S
Akiyama
D018053:Arsenites / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D015342:DNA Probes; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017670:Sodium Compounds / Q000494:pharmacology*
D018053:Arsenites; D015342:DNA Probes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017670:Sodium Compounds; C017947:sodium arsenite; C421109:multidrug resistance-associated protein 1