RT Journal Article
SR Electronic
T1 Collateral Sensitivity to Cisplatin in KB-8-5-11 Drug-resistant Cancer Cells
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 503
OP 507
VO 34
IS 1
A1 BEN DOHERTY
A1 DENISE LAWLOR
A1 JEAN-PIERRE GILLET
A1 MICHAEL GOTTESMAN
A1 JOHN J. O'LEARY
A1 BRITTA STORDAL
YR 2014
UL http://ar.iiarjournals.org/content/34/1/503.abstract
AB Background: KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer. Materials and Methods: A Taqman low-density array was used to characterize the expression of 380 genes previously associated with chemoresistance. Identified pathways were further analyzed using cytotoxicity assays, metabolomics and western blots. Results: KB-8-5-11 cells were sensitive to CuSO4 and the glutathione inhibitor buthionine sulphoximine. Expression of ATPase, Cu2+ transporting alpha (ATP7A) and ATP7B were decreased at the protein and gene levels respectively in KB-8-5-11. KB-8-5-11 had decreased gene expression of glutathione S-transferase pi 1 (GSTP1), GSTA4 and GSTK1. Cisplatin treatment significantly lowered total cellular glutathione in parental KB-3-1 cells. Glutathione also tended to be lower in KB-8-5-11 cells compared to KB-3-1 cells. Conclusion: KB-8-5-11 cells have alterations in their copper transporters and glutathione metabolism, contributing to their cisplatin-sensitive phenotype.