An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant humanKB carcinoma cells

Citation
Zs. Chen et al., An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant humanKB carcinoma cells, CANCER LETT, 138(1-2), 1999, pp. 13-22
Citations number
31
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
CANCER LETTERS
ISSN journal
03043835 → ACNP
Volume
138
Issue
1-2
Year of publication
1999
Pages
13 - 22
Database
ISI
SICI code
0304-3835(19990426)138:1-2<13:AEAEOC>2.0.ZU;2-1
Abstract
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 m echanism 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 nor expressed in KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Ch uman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The a ccumulation 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 lin es was also similar. The transport of LTC4 in KCP-4 membrane vesicles was c ompetitively inhibited by bis-(glutathionato)platinum (II) (GS-Pt), CPT-11 and SN-38. These findings suggested that an unknown transporter distinct fr om P-gp, MRP or cMOAT is expressed in KCP-3 cells and transports CPT-11 and SN-38. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.