TY - JOUR
T1 - Annamycin circumvents resistance mediated by the multidrug resistance-associated protein (MRP) in breast MCF-7 and small-cell lung UMCC-1 cancer cell lines selected for resistance to etoposide
AU - Perez-Soler, Roman
AU - Neamati, Nouri
AU - Zou, Yiyu
AU - Schneider, Erasmus
AU - Doyle, L. Austin
AU - Andreeff, Michael
AU - Priebe, Waldemar
AU - Ling, Yi He
PY - 1997
Y1 - 1997
N2 - Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that has been shown to circumvent MDR-I both in vitro and in vivo. A liposomal formulation of Ann is currently in phase 1 clinical trials. The multidrug resistance-associated protein (MRP) has been found to be over-expressed in some human leukemias at relapse and to be a poor prognostic factor in neuroblastoma. We studied the in vitro cytotoxicity and the cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs of human cell lines, breast carcinoma MCF7 and small-cell lung cancer UMCC-1, and their MRP-expressing counterparts, MCF-7/VP and UMCC-I/VP. Resistance indexes were 1.1 and 1,4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive cells. By confocal microscopy, the subcellular distribution of Ann was identical in sensitive and resistant cells, localizing mostly in the perinuclear structures, while that of Dox was exclusively nuclear in sensitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our results indicate that Ann may be effective in the treatment of malignancies in which MRP is a relevant mechanism of clinical resistance.
AB - Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that has been shown to circumvent MDR-I both in vitro and in vivo. A liposomal formulation of Ann is currently in phase 1 clinical trials. The multidrug resistance-associated protein (MRP) has been found to be over-expressed in some human leukemias at relapse and to be a poor prognostic factor in neuroblastoma. We studied the in vitro cytotoxicity and the cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs of human cell lines, breast carcinoma MCF7 and small-cell lung cancer UMCC-1, and their MRP-expressing counterparts, MCF-7/VP and UMCC-I/VP. Resistance indexes were 1.1 and 1,4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive cells. By confocal microscopy, the subcellular distribution of Ann was identical in sensitive and resistant cells, localizing mostly in the perinuclear structures, while that of Dox was exclusively nuclear in sensitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our results indicate that Ann may be effective in the treatment of malignancies in which MRP is a relevant mechanism of clinical resistance.
UR - http://www.scopus.com/inward/record.url?scp=0030887296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030887296&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1097-0215(19970328)71:1<35::AID-IJC8>3.0.CO;2-4
DO - 10.1002/(SICI)1097-0215(19970328)71:1<35::AID-IJC8>3.0.CO;2-4
M3 - Article
C2 - 9096663
AN - SCOPUS:0030887296
SN - 0020-7136
VL - 71
SP - 35
EP - 41
JO - International journal of cancer
JF - International journal of cancer
IS - 1
ER -