New silicon compounds as resistance modifiers against multidrug-resistant cancer cells.
The efficiency of chemotherapy is often decreased by the development of resistance of cancer cells to cytostatic drugs. This phenomenon is in most cases caused by the activity of the various ABC transporters, multidrug-resistance (MDR) gene-encoded p-glycoproteins, that pump anticancer drugs out of the cells. The inhibition of the activities of the MDR proteins MDR1 and MRP was investigated via the administration of two new organosilicon compounds, alis-409 and alis-421. The study was focused on the inhibition of MDR by blocking the ADR1 gene expression and through the inhibition of the pump-function of mdr-p-glycoprotein, in human breast cancer cell lines expressing mrp and prostate cancer cell line (PC-3). Apoptosis induction and the interaction between epirubicin and the silicon-substituted compounds were studied in human MDR-1 gene-transfected mouse lymphoma and its parent cell line, Colo320/MDR-LRP and sensitive subline Colo205, by means of rhodamine 123 accumulation. The activity of MRP1 p-glycoprotein was studied in human breast cancer cell lines such as HTB-26/MRP1 and two MRP-negative breast cancer cell lines, T47D and MCF7, by carboxyfluorescein accumulation, and on a stomach cancer cell line. The activity of MRP in 257P/MDR and its drug-sensitive derivative were studied in human stomach cancer cells by daunorubicin accumulation in a flow cytometer. The two representative organosilicon derivatives, alis-409 and alis-421, showed antiproliferative effects without apoptosis induction. The drug accumulation in the human MDR1 gene-transfected mouse lymphoma cells was increased without down-regulation of the MDR1 gene expression tested by RT-PCR assay. The rhodamine uptake was increased in L5178/MDR1 and Colo320/MDR1-LRP, but not drug-sensitive human breast cancer MCF-7 and T47D, and L5178 mouse lymphoma parent cells in the presence of alis-409 and alis-421. The MRP-mediated carboxyfluorescein accumulation in HTB-26/MRP human breast cancer cells and daunorubicin accumulation in human stomach cancer cells 257P/MDR were not modified by these alis compounds. A synergistic interaction between epirubicin and the silicon-substituted resistance modifiers was found only in MDR1-mediated MDR in the case of colo-320/MDR1-LRP cells and mouse lymphoma cells transfected with the human MDR1 gene. The results indicate that the organosilyl derivatives specifically act on MDR1 p-glycoprotein 170. The alis compounds act on pgp170 in a way which is similar to verapamil isomers.
Molnar
J
J
Albert Szent-Györgyi Medical Center, Faculty of Medicine, Institute of Microbiology, University of Szeged, Hungary. molnarj@comser.szote.u-szeged.hu
Mucsi
I
I
Nacsa
J
J
Hevér
A
A
Gyémánt
N
N
Ugocsai
K
K
Hegyes
P
P
Kiessig
St
S
Gaal
D
D
Lage
H
H
Varga
A
A
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D015251:Epirubicin / Q000494:pharmacology; D005452:Fluoresceins / Q000493:pharmacokinetics; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017646:Organosilicon Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014162:Transfection
D005452:Fluoresceins; D017646:Organosilicon Compounds; D020112:Rhodamine 123; C024098:6-carboxyfluorescein; D015251:Epirubicin