The effect of fatty acids and analogues upon intracellular levels of doxorubicin in cells displaying P-glycoprotein mediated multidrug resistance.

Abstract

Multidrug resistance mediated by overexpression of P-glycoprotein (P-gp) is a major obstacle in the chemotherapeutic management of cancer. The objectives of the current work were to examine if fatty acids affect the intracellular transport and dynamics of doxorubicin in drug-resistant cancer cell lines, and to assess if such effects were mediated through modulation of P-gp efflux pump activity. Among the range of fatty acids tested in this study, eicosapentaenoic acid diester (EPADI) increased doxorubicin accumulation [A] to 137% and retention [R] to 212% in doxorubicin-resistant MCF-7/ADR breast carcinoma cells, and [A] to 147% and [R] to 163% in vinblastine-resistant KBVI nasopharyngeal carcinoma cells. Consistent with EPADI-induced increases in intracellular doxorubicin concentrations, EPADI (10 microg/ml) sensitized MCF-7/ADR cells to the cytotoxic effects of doxorubicin (1 microg/ml) as assessed by MTT assay (viability < 50% of control), while EPADI itself displayed no cytotoxicity. The combination of EPADI (10 microg/ml) with verapamil (1 microM) resulted in a considerable increase in the [A] and [R] of the model P-gp substrate rhodamine-123 within drug-resistant cells compared to when either agent were used alone. KBV1 cells treated with combination of EPADI (10 microg/ml) and verapamil (1 microM) achieved 160% and 1120% greater [A] and [R] of rhodamine-123, respectively, compared to untreated cells. The P-gp modulatory effects of EPADI either alone, or as part of a combination with more potent inhibitors, should be further investigated.

• Authors: A N Abulrob, M Mason, R Bryce, M Gumbleton
• Journal: Journal of drug targeting (J Drug Target) Vol. 8 Issue 4 Pg. 247-56 ( 2000) ISSN: 1061-186X [Print] England
• PMID: 11144235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• Fatty Acids, Unsaturated
• eicosapentaenoic acid diester
• Rhodamine 123
• Doxorubicin
• Eicosapentaenoic Acid
• Verapamil

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, biosynthesis, metabolism)
• Antibiotics, Antineoplastic (pharmacokinetics, toxicity)
• Biological Transport, Active (drug effects)
• Doxorubicin (pharmacokinetics, toxicity)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Drug Synergism
• Eicosapentaenoic Acid (analogs & derivatives, pharmacology)
• Fatty Acids, Unsaturated (pharmacology)
• Humans
• Rhodamine 123 (pharmacokinetics)
• Tumor Cells, Cultured (drug effects, metabolism)
• Verapamil (pharmacology)