Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2.

Abstract

The phenomenon of multidrug resistance (MDR) in human cancers is one of the major causes of failure of chemotherapy. A recently identified new member of the superfamily of ATP-binding cassette transporters, breast cancer resistance protein (BCRP), was demonstrated to confer an atypical multidrug-resistant phenotype to tumor cells. To overcome the BCRP-mediated drug resistance, a specific anti-BCRP hammerhead ribozyme was introduced into the human gastric carcinoma cell line, EPG85-257RNOV, exhibiting an atypical MDR phenotype. By this approach, the expression levels of the targeted BCRP-encoding mRNA and the BCRP transport protein were decreased to the low constitutive expression level that was observed in highly drug-sensitive parental gastric carcinoma cells. In addition, in the anti-BCRP ribozyme-treated cells, the cellular drug accumulation was dramatically increased to the level measured in drug-sensitive cells. These effects were accompanied by an extensive reversal of the drug-resistant phenotype of more than 80%. Because additional mechanisms contribute to the multimodal-mediated MDR phenotype exhibited by this gastric carcinoma cell line, the data suggest that the BCRP-mediated contingent to the drug resistance was overcome nearly completely. Moreover, the data indicate that ribozyme-based gene therapy may be clinically applicable in preventing and reversing BCRP-mediated atypical MDR.

• Authors: Petra Kowalski, Ulrike Stein, George L Scheffer, Hermann Lage
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 9 Issue 7 Pg. 579-86 (Jul 2002) ISSN: 0929-1903 [Print] England
• PMID: 12082458 (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
• Antibiotics, Antineoplastic
• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Neoplasm Proteins
• Peptides
• RNA, Catalytic
• RNA, Messenger
• hammerhead ribozyme
• Etoposide
• Mitoxantrone
• Cisplatin
• Daunorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Base Sequence
• Cell Division
• Cell Survival
• Cell-Free System
• Cisplatin (pharmacology)
• Daunorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Etoposide (pharmacology)
• Flow Cytometry
• Humans
• Mitoxantrone (pharmacology)
• Molecular Sequence Data
• Neoplasm Proteins
• Peptides (pharmacology)
• Phenotype
• Plasmids (metabolism)
• RNA, Catalytic (metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (drug therapy)
• Time Factors
• Transfection
• Tumor Cells, Cultured