In vitro and in vivo multidrug resistance reversal activity by a Betti-base derivative of tylosin.
BACKGROUND
The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin.


METHODS
Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines.


RESULTS
In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect.


CONCLUSIONS
Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers.
Gyémánt
N
N
Faculty of Medicine, Institute of Medical Microbiology and Immunobiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
Engi
H
H
Schelz
Z
Z
Szatmári
I
I
Tóth
D
D
Fülöp
F
F
Molnár
J
J
de Witte
P A M
PA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D009284:Naphthols / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism; D014162:Transfection; D015645:Tylosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007783:Lactones; C551229:N-tylosil-1-amino-(3-bromophenyl)methyl-2-naphthol; D009284:Naphthols; D020112:Rhodamine 123; D004317:Doxorubicin; D015645:Tylosin