Effect of organic isothiocyanates on breast cancer resistance protein (ABCG2)-mediated transport.

Abstract

PURPOSE:

To investigate the effect of organic isothiocyanates (ITCs), dietary compounds with chemopreventive activity, on breast cancer resistance protein (BCRP)-mediated transport.

METHODS:

The effect of 12 ITCs on the cellular accumulation of mitoxantrone (MX) was measured in both BCRP-overexpressing and BCRP-negative human breast cancer (MCF-7) and large cell lung carcinoma (NCI-H460) cells by flow cytometric analysis. The ITCs showing activity in MX accumulation were examined for their effect on MX cytotoxicity, and the intracellular accumulation of radiolabeled phenethyl isothiocyanate (PEITC) was measured in both BCRP-overexpressing and BCRP-negative NCI-H460 cells.

RESULTS:

ITCs significantly increased MX accumulation and reversed its cytotoxicity in resistant cells, but had a small or no effect in sensitive cells. The effects of ITCs on MX accumulation and cytotoxicity were ITC-concentration dependent. Significant increases in MX accumulation were observed at ITC concentrations of 10 or 30 microM, and significant reversal of MX cytotoxicity was generally observed at ITC concentrations of 10 microM. Intracellular accumulation of radiolabeled PEITC in BCRP-overexpressing cells was significantly lower than that in BCRP-negative cells and was increased significantly by the BCRP inhibitor fumitremorgin C (FTC).

CONCLUSIONS:

Certain ITCs are BCRP inhibitors and PEITC and/or its cellular metabolite(s) may represent BCRP substrates, suggesting the potential for diet-drug interactions.

• Authors: Yan Ji, Marilyn E Morris
• Journal: Pharmaceutical research (Pharm Res) Vol. 21 Issue 12 Pg. 2261-9 (Dec 2004) ISSN: 0724-8741 [Print] United States
• PMID: 15648258 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Isothiocyanates
• Neoplasm Proteins
• Methotrexate

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (biosynthesis, pharmacokinetics, physiology)
• Breast Neoplasms (metabolism)
• Cell Survival (drug effects, physiology)
• Dose-Response Relationship, Drug
• Humans
• Isothiocyanates (pharmacology)
• Methotrexate (pharmacokinetics)
• Neoplasm Proteins (biosynthesis, pharmacokinetics, physiology)
• Protein Transport (drug effects, physiology)
• Tumor Cells, Cultured