Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF-7 human breast-cancer cells

✍ Scribed by Rosa De Vincenzo; Giovanni Scambia; Pierluigi Benedetti Panici; Andrea Fattorossi; Giuseppina Bonanno; Cristiano Ferlini; Giulio Isola; Stefania Pernisco; Salvatore Mancuso

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 865 KB
• Volume: 68
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19961104)68:3<340::aid-ijc12>3.0.co;2-c

✦ Synopsis

In this study the ability of the new pure anti-estrogen IcI 182,780 to modulate the cytotoxic action of adriamycin (ADR) on parental and ADR-resistant MCF-7 (MCF-7 ADRr) human breast-cancer cells was investigated and compared with that of tamoxifen (TAM). TAM enhanced ADR cytotoxicity in MCF-7 ADRr cells in a dose-related manner, but this effect was slight or absent in MCF-7 WT. In contrast, ICI 182,780 was able to enhance ADR toxicity both in MCF-7 ADRr and in the parental cell line. ICI 182,780 was up to 2.5-fold more effective than TAM in reducing the lCW of ADR in MCF-7 ADRr cells. Analysis of the data by the isobole method showed that the combination ADR/TAM and ADR/ICI 182,780 produced synergistic antiproliferative activity in MCF-7 ADRr cells. Because ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of anti-estrogens on Pgp expression and activity. Both ICI 182,780 and TAM failed to modulate Pgp expression as assessed by flow cytometry and Westem-blot analysis, performed using the monoclonal antibodies MM4. I7 and C 2 19, which are specific for an external or M internal determinant respectively. Pgp activity was investigated by flow cytometry measuring the extrusion of ADR and the cationic dye Rhodamine I23 (Rh 123). ICI 182,780, but not TAM, reduced the activity of Pgp in MCF-7 ADRr cells. Flow cytometry was also used to investigate cell-cycle modifications induced by ADR in MCF-7 ADRr cells, both in the presence and in the absence of anti-estrogens. After 72 hr, higher doses induced an arrest of cells at the G2/M phase. The same effect was visible when lower doses of ADR were combined with ICI 182,780 or TAM. In terms of cell-cycle-blocking activity ICI 182,780 was largely more effective than TAM.