Combined effect of bis-beta-chloroethylamine estrogen derivatives and doxorubicin on proliferation of sensitive and resistant MCF-7 cells.
The sensitivity of normal (MCF-7/WT) and doxorubicin-resistant (MCF-7/R) breast cancer cells to the antiproliferative effect of ethynylestradiol 11alpha-derivatives with the cytostatic residue in the 3-position of the steroid ring (antiestrogen cytostatics) was studied by evaluating cell viability using methylthiazole tetrazolium staining. The antiproliferative effects of these agents on cell lines in the presence of doxorubicin were compared. Antiestrogen cytostatics produced weaker cytostatic effect on MCF-7/WT cells, but more potent cytostatic effect on MCF-7/WT cells compared to those of doxorubicin. Moreover, administration of these agents in combination with doxorubicin more significantly suppressed proliferation of tumor cells. Accumulation and efflux of cytostatic doxorubicin in MCF-7/R cells were studied in the presence and absence of antiestrogen cytostatic Po716. Confocal laser microscopy showed that doxorubicin accumulation in MCF-7/R cells in the absence of Po716 took 20 min, while in the presence of antiestrogen cytostatic this process took 5 min. The rate of doxorubicin transport from tumor cells was much lower in the presence of the test antiestrogen cytostatic. Our results suggest that antiestrogen cytostatics increase the sensitivity of resistant MCF-7/R cells to doxorubicin by modulating the mechanisms of multidrug resistance of tumor cells.
Mayatskaya
E E
EE
Department of Molecular Pharmacology and Radiobiology, Russian State Medical University, Moscow.
Shimanovskii
N L
NL
Banin
V V
VV
Fedotcheva
T A
TA
Semeikin
A V
AV
Rzheznikov
V M
VM
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D045166:Estradiol Congeners / Q000008:administration & dosage*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans
D000903:Antibiotics, Antineoplastic; D045166:Estradiol Congeners; D020847:Estrogen Receptor Modulators; D004997:Ethinyl Estradiol; D004317:Doxorubicin