Homocamptothecin-Daunorubicin Association Overcomes Multidrug-Resistance in Breast Cancer MCF7 Cells
- 1 May 2002
- journal article
- Published by Springer Science and Business Media LLC in Breast Cancer Research and Treatment
- Vol. 73 (2), 113-125
- https://doi.org/10.1023/a:1015244604336
Abstract
The multidrug-resistance (MDR) status of a novel camptothecin analogue, homocamptothecin (hCPT), was investigated in human colon adenocarcinoma HT29 cells, myelogenous leukemia K562 cells and breast carcinoma MCF7 cells. The cytotoxicity of hCPT was not sensitive to the MDR status in K562 cell lines. However, its cytotoxicity was altered by MRP1, but not Pgp, in naturally MRP1-expressing HT29 cells, and etoposide- and doxorubicin-resistant MCF7/VP and MCF7/DOX cells, respectively. These cells were sensitized to hCPT in presence of MK571, probenecid but not verapamil. These results led to consider hCPT as a substrate for MRP1 and a potential modulator of MRP1 activity. The relationship between the cytotoxic effect of anthracyclines and their nuclear localization had been previously demonstrated. We show that MRP1 mediated the daunorubicin (DNR) efflux in MCF7/VP and MCF7/DOX cells. The combination of sub-toxic doses of hCPT with DNR resulted in the potentiation of DNR activity, well-correlated with an increase in its nuclear accumulation in MCF7/VP cells. Simultaneous pattern was shown to provide higher cytotoxic response than sequential one. In agreement, hCPT increased also the DNR nuclear accumulation in low MRP1-expressing MCF7/DOX cells. However, the enhancement of cytotoxicity in the DNR-hCPT combination was poorly correlated with the nuclear concentration of DNR in MCF7/DOX cells. In addition to the increase in DNR accumulation, the potentiation of DNR activity by hCPT in MCF7/DOX cells implied a synergistic mechanism between both drugs. These data suggest that the present topoisomerase I/II inhibitors combination may be of clinical interest to overcome MDR phenotype in DNR-treated breast cancer patients.Keywords
This publication has 36 references indexed in Scilit:
- Chemotherapy of Metastatic Breast Cancer: What to Expect in 2001 and BeyondThe Oncologist, 2001
- Structural, mechanistic and clinical aspects of MRP1Biochimica et Biophysica Acta (BBA) - Biomembranes, 1999
- CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated proteinBritish Journal of Cancer, 1998
- Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patientsBritish Journal of Cancer, 1997
- Anthracycline subcellular distribution in human leukemic cells by microspectrofluorometry: factors contributing to drug-induced cell death and reversal of multidrug resistanceLeukemia, 1997
- P-glycoprotein—A mediator of multidrug resistance in tumour cellsEuropean Journal Of Cancer, 1996
- EpirubicinDrugs, 1993
- Role of the aclacinomycin A – doxorubicin association in reversal of doxorubicin resistance in K562 tumour cellsBritish Journal of Cancer, 1989
- Quantitative study of doxorubicin in living cell nuclei by microspectrofluorometryBiochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1988
- Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivityInternational Journal of Radiation Oncology*Biology*Physics, 1979