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.