An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells.
Cisplatin-resistant KCP-4 cells were 12.4- and 31.6-fold more resistant to CPT-11 and SN-38 than parental KB-3-1 cells, respectively. We studied the mechanism of cross-resistance to CPT-11 and SN-38. Our previous study showed that multidrug resistance protein (MRP), canalicular multispecific organic anion transporter (cMOAT) and P-glycoprotein (P-gp) were not expressed in KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Chuman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The accumulation of both CPT-11 and SN-38 in KCP-4 cells was lower than that in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from KCP-4 cells was enhanced compared with that from KB-3-1 cells. DNA topoisomerase (topo) I expression, topo I activity, topo I-mediated cleavable complex, and the sensitivity to SN-38 of DNA topo I in KCP-4 were similar to those in KB-3-1 cells. Furthermore, the conversion of CPT-11 to SN-38 in the two cell lines was also similar. The transport of LTC4 in KCP-4 membrane vesicles was competitively inhibited by bis-(glutathionato)-platinum (II) (GS-Pt), CPT-11 and SN-38. These findings suggested that an unknown transporter distinct from P-gp, MRP or cMOAT is expressed in KCP-4 cells and transports CPT-11 and SN-38.
Chen
Z S
ZS
Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Japan.
Sumizawa
T
T
Furukawa
T
T
Ono
K
K
Tani
A
A
Komatsu
M
M
Akiyama
S
S
D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077146:Irinotecan; D007624:KB Cells; D017997:Leukotriene C4 / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D002945:Cisplatin; D004247:DNA; D004264:DNA Topoisomerases, Type I; D000077146:Irinotecan; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins