Partial circumvention of multi-drug resistance by annamycin is associated with comparable inhibition of DNA synthesis in the nuclear matrix of sensitive and resistant cells.
We studied the subcellular and subnuclear distributions of the partially cross-resistant anthracycline Annamycin (Ann) in KB-3-1 and multi-drug resistant KB-VI cells. Subcellular drug localization was assessed qualitatively by fluorescence microscopy and quantitatively by cell fractionation and fluorescence measurements. Doxorubicin (Dox) localized predominantly in the nucleus in KB-3-1 cells and in the membranes in KB-VI cells. In contrast, the subcellular distribution of Ann was identical in both cell lines, with preferential drug localization in the perinuclear region, Golgi apparatus, endoplasmic reticulum and endosomes. Dox rate of efflux from the nucleus was negligible in KB-3-1 cells but markedly enhanced in KB-VI cells, whereas Ann was lost at a similar rate from the nucleus in both cell lines. In KB-3-1 cells Dox levels in the nuclear non-matrix were about 2-fold higher than those of Ann, while in the matrix the inverse relationship was observed. In spite of these differences, Dox and Ann had a similar inhibitory effect on new DNA synthesis in the nuclear matrix and non-matrix of KB-3-1 cells. Dox levels were reduced by 10-fold in the nuclear non-matrix and 2-fold in the matrix in KB-VI cells compared with KB-3-1 cells, whereas Ann levels were reduced by about 2- to 3-fold in the non-matrix and were unchanged in the matrix. In correlation with these findings, Dox did not cause inhibition of new DNA synthesis in either nuclear fraction in KB-VI cells, whereas inhibition of new DNA synthesis in the matrix by Ann was similar in both cell lines. Our results indicate that Ann's partial circumvention of multi-drug resistance is associated with its ability to cause comparable new DNA synthesis inhibition in the nuclear matrix of sensitive and resistant cells.
Ling
Y H
YH
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Zou
Y
Y
Priebe
W
W
Perez-Soler
R
R
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D018432:Drug Resistance, Multiple; D006801:Humans; D007624:KB Cells; D008856:Microscopy, Fluorescence; D008985:Monensin / Q000494:pharmacology; D015530:Nuclear Matrix / Q000187:drug effects / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004317:Doxorubicin; D016572:Cyclosporine; D008985:Monensin; D014700:Verapamil; C080315:annamycin