Breast Cancer Resistance Protein Directly Confers SN-38 Resistance of Lung Cancer Cells

Biochem Biophys Res Commun. 2001 Feb 9;280(5):1216-23. doi: 10.1006/bbrc.2001.4267.

Abstract

Breast cancer resistance protein (BCRP), an ABC half-transporter, is overexpressed in cancer cell lines selected with doxorubicin/verapamil, topotecan, or mitoxantrone. BCRP-overexpressing cells show cross-resistance to camptothecin derivatives such as irinotecan, SN-38 (the active metabolite of irinotecan), and topotecan. To test whether BCRP confers SN-38 resistance, we selected two SN-38 resistant sublines from PC-6 human small-cell lung cancer cells by SN-38, and then characterized these cells. Compared to PC-6 cells, the resistant sublines PC-6/SN2-5 and PC-6/SN2-5H were approximately 18- and 34-fold resistant, respectively. The intracellular SN-38 accumulation was reduced in the sublines, and BCRP mRNA was overexpressed in proportion to the degree of SN-38 resistance. These findings suggest that BCRP confers SN-38 resistance in the sublines. To confirm this hypothesis, PC-6/SN2-5 cells were transfected with antisense oligonucleotides complementary to portions of BCRP mRNA. The antisense oligonucleotides significantly suppressed BCRP mRNA expression, and enhanced SN-38 sensitivity in the subline. These data indicate that BCRP is directly involved with SN-38 resistance, by efflux transport of SN-38.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Blotting, Northern
  • Caco-2 Cells
  • Camptothecin / analogs & derivatives
  • Camptothecin / metabolism
  • Camptothecin / pharmacology*
  • DNA, Antisense / genetics
  • DNA, Antisense / physiology
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Irinotecan
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Neoplasm Proteins*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transfection
  • Tumor Cells, Cultured / drug effects

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents, Phytogenic
  • DNA, Antisense
  • Neoplasm Proteins
  • RNA, Messenger
  • Irinotecan
  • Camptothecin