(-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line

• Published in: Phytomedicine (Stuttgart) Vol. 17; no. 5; pp. 356 - 362
• Main Authors: Farabegoli, F., Papi, A., Bartolini, G., Ostan, R., Orlandi, M.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.04.2010; Urban & Fischer Verlag
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; bcl-2-Associated X Protein - metabolism; BCRP; Breast cancer; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Camellia sinensis - chemistry; Care and treatment; Catechin - analogs & derivatives; Catechin - pharmacology; Catechin - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm - drug effects; Gene Expression; Genetic aspects; Green tea; Health aspects; Humans; Isoflavones; Leupeptins - pharmacology; Mitoxantrone - pharmacology; MRP1; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; P-gp; Physiological aspects; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Protease Inhibitors - pharmacology; Protease Inhibitors - therapeutic use; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Messenger - metabolism; Tamoxifen; Italy; BCRP; Breast carcinoma; MRP1; P-gp; MCF-7Tam; EGCG; Tamoxifen; Green tea; ER α
• ISSN: 0944-7113; 1618-095X; 1618-095X
• DOI: 10.1016/j.phymed.2010.01.001

We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100 μg/ml for 24-72 hours) caused cell growth inhibition and dose-dependent apoptosis: after 100 μg/ml EGCG treatment for 24 hours, Bax expression increased and Bcl2 expression decreased (p<0.05). Coherently, Annexin V-FITC apoptosis assay detected a significant increase in labelled cells (p<0.05). EGCG did not affect MRP1: in contrast, 100 μg/ml EGCG administration caused P-gp decrease to 53% of control cells (p<0.001) and this effect was not due to downregulation of P-gp gene expression. EGCG induced P-gp decrease even when MG132, a strong proteasome inhibitor, was given together with EGCG to MCF-7Tam cells. EGCG treatment also inhibited BCRP activity: mRNA transcription and protein level did not change after treatment, but mitoxantrone test demonstrated a strong inhibition of BCRP activity (p<0.001). In conclusion, the present results showed that EGCG could down-regulate the activity of two molecules that play a key role in drug metabolism and transport and that are highly expressed in tamoxifen resistant breast carcinoma cells. The interaction of EGCG and drugs used in the therapy of estrogen sensitive breast carcinoma ought to be subject of studies and the potential use of EGCG in drug-resistant diseases ought to be better considered.