Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells

Doherty, Ben, Lawlor, Denise, Gillet, Jean-Pierre, Gottesman, Michael, O'Leary, John J. and Stordal, Britta K. ORCID: https://orcid.org/0000-0002-7892-951X (2014) Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells. Anticancer Research, 34 (1) . pp. 503-507. ISSN 0250-7005 [Article]

Abstract

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, Cu(2+) 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.

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