P-glycoprotein mediates profound resistance to bisantrene.
Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.
Zhang
X P
XP
Oncology and Immunology Research Section, Lederle Laboratories, Division of American Cyanamid, Pearl River, NY 10965.
Ritke
M K
MK
Yalowich
J C
JC
Slovak
M L
ML
Ho
J P
JP
Collins
K I
KI
Annable
T
T
Arceci
R J
RJ
Durr
F E
FE
Greenberger
L M
LM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002871:Chromosome Banding; D002877:Chromosomes, Human; D002999:Clone Cells; D003110:Colonic Neoplasms; D017931:DNA Primers; D018432:Drug Resistance, Multiple; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007624:KB Cells; D008545:Melanoma; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D017931:DNA Primers; D011994:Recombinant Proteins; C031404:bisantrene