The synergistic anti-tumour activity of ICI 182,780 in combination with docetaxel is mediated by P-glycoprotein inhibition

in Endocrine-Related Cancer
Authors:
C Ferlini Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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M Di Stefano Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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M Marone Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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C Gaggini Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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G Ferrandina Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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A Riva Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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E Bombardelli Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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A De Pasqua Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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S Mancuso Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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G Scambia Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
INDENA, SpA, Milan, Italy
ZENECA, Milan, Italy

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Volume/Issue:
Volume 5: Issue 4
Article Type:
Research Article
Page Range:
315–324
Online Publication Date:
Dec 1998
Copyright:
Society for Endocrinology 1998
Free access

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Abstract

Docetaxel is a semi-synthetic drug that has been shown to be effective in refractory advanced breast cancer. Its main mechanism of action seems to be to block microtubule depolymerisation. In this study we investigated the interaction between docetaxel and the pure anti-oestrogen ICI 182,780 on different oestrogen receptor-negative cancer cells, some of which express the classical multi-drug resistance (MDR) phenotype. ICI 182,780 potentiated the anti-proliferative effect of docetaxel only in the MDR-positive cells. Isobolic analysis demonstrated that this chemosensitising effect was a synergism. In the same conditions where synergism was detected, cell cycle analysis demonstrated an augmentation of cells blocked at the G2/M phase of the cell cycle, suggesting that ICI 182,780 increases the activity of docetaxel. In order to test this hypothesis, we performed bcl-2 western blot analysis and demonstrated that the addition of ICI 182,780 to docetaxel induced bcl-2 phosphorylation only in MDR-positive cells. The functional inactivation of bcl-2 is probably responsible for the commitment to apoptosis, since the combined docetaxel/ICI 182,780 treatment was able to foster a massive apoptosis in MDR-bearing cells as demonstrated by morphological analysis.

Our results suggest that the synergism between docetaxel and ICI 182,870 is due to a block in P-glycoprotein activity, thus determining cell cycle block, bcl-2 inactivation and apoptosis induced by docetaxel accumulation.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
Society for Endocrinology 1998
Page(s):
10
Print Publication Date:
01 Dec 1998
Online Publication Date:
Dec 1998