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

Anticancer Res. 2014 Jan;34(1):503-7.

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.

Keywords: Cisplatin; KB-8-5-11 cells; cervical cancer; collateral sensitivity; drug resistance; paclitaxel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Proliferation / drug effects*
  • Cisplatin / pharmacology*
  • Copper-Transporting ATPases
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glutathione / metabolism
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Metabolomics
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Cation Transport Proteins
  • RNA, Messenger
  • GSTK1 protein, human
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • Adenosine Triphosphatases
  • leukotriene-C4 synthase
  • ATP7A protein, human
  • ATP7B protein, human
  • Copper-Transporting ATPases
  • Glutathione
  • Cisplatin