Breast cancer resistance protein-mediated topotecan resistance in ovarian cancer cells.

Abstract

Overexpression of breast cancer resistance protein (BCRP) and mitoxantrone (MX) resistance protein can confer resistance to a variety of cytostatic drugs, such as MX, topotecan (TPT), doxorubicin, and daunorubicin. This study investigates the role of BCRP in resistance of ovarian cancer to TPT treatment. We have developed TPT-resistant human ovarian cancer cell line. Intracellular concentration of fluorescent dye rhodamine 123 (Rh123) was measured by flow cytometry. The expression of several membrane transporter proteins including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and BCRP were determined by reverse transcription-polymerase chain reaction and Western blotting. The Rh123 concentration in parental cells was approximately three times of those in TPT-resistant cells. In contrast to undetectable level of P-gp messenger RNA (mRNA) and minimal level of MRP1 expression in TPT-resistant cells, overexpression of both the BCRP mRNA and the protein was detected in these cells. Introduction of antisense-phosphorothioate oligonucleotide derived from BCRP mRNA into TPT-resistant cells resulted in a significant increase in the concentration of intracellular Rh123. These results suggested a novel mechanism in which a reduced intracellular drug concentration may be mediated by BCRP gene products in human ovarian cancer cells.

• Authors: P Jia, S Wu, F Li, Q Xu, M Wu, G Chen, G Liao, S Wang, J Zhou, Y Lu, D Ma
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) 2005 Nov-Dec Vol. 15 Issue 6 Pg. 1042-8 ISSN: 1048-891X [Print] England
• PMID: 16343180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Membrane Transport Proteins
• Neoplasm Proteins
• Oligodeoxyribonucleotides, Antisense
• Topotecan

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gene Expression
• Humans
• Membrane Transport Proteins
• Neoplasm Proteins (genetics)
• Oligodeoxyribonucleotides, Antisense (genetics)
• Ovarian Neoplasms (genetics)
• Topotecan (pharmacology)
• Transfection