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ABSTRACT
We have evaluated the effect of the quinazolinone derivatives
on P-glycoprotein-mediated MDR in breast cancer by performing
an in vitro cytotoxicity assay and flow cytometry. The cell
lines employed for this study were human breast cancer cells
selected for
resistance to adriamycin, MCF7/adr, and its counterpart,
wildtype MCF7. Compared with the sensitivity of the wildtype
and adr-resistant cells, the MCF7/adr subline showed more than
a sevenfold increase in resistance to adriamycin at 1uM. We
have used the p
air of MCF7 cells to assess the cytotoxic activity of a series
of quinazolinone derivatives. In both cell lines, DQ-181 was
the most potent cytotoxic agent using MTT assay, while the
other compounds did not present significant activity. When the
pair of MCF7 cells were treated with adriamycin, DQ-150 and
EY-057 at 1uM could enhance cytotoxic activity of adriamycin in
MCF7/adr, indicating that these compounds could reverse drug
resistance induced by adriamycin.
For investigation of the mechanism of DQ-150 and EY-057 on drug
resistance reversal, rhodamine 123 accumulation was detected in
the pair of MCF7 cells. One uM DQ-150 has a twofold increase in
intracellular rhodamine 123 in MCF7/adr cells, compared with
the control. In contrast, we did not observe the high level of
rhodamine 123 accumulation in the pair of MCF7 cells treated
with EY-057 at 1uM.
In addition to enhancement of anticancer drug transportation,
other mechanisms of drug resistance reversal have been studied.
Apoptosis is the end point of cells exposed to chemotherapeutic
agents and is part of normal homeostasis. In our study, an
increase in apoptosis was observed in adriamycin-treated MCF7/
adr cells when exposed to DQ-150 or EY-057 for 4 days using
flow cytometry. DQ-150 and EY-057 at 1uM could enhance
apoptosis by a 3-fold and 1.5-fold, respectively, in MCF7/adr
treated with adriamycin.
sults demonstrates that DQ-150 or EY-057 sensitize the
in vitro cytotoxicity of adriamycin in MCF7/adr cells. The
mechanisms of drug resistance reversal may vary, depending on
the structure of compounds. DQ-150 increases the intracellular
accumulation of rhodamine 123 in MCF7/adr,
Results demonstrates that DQ-150 or EY-057 sensitize the in
vitro cytotoxicity of adriamycin in MCF7/adr cells. The
mechanisms of drug resistance reversal may vary, depending on
the structure of compounds. DQ-150 increases the intracellular
accumulation of rhodamine 123 in MCF7/adr,
indicating DQ-150 potentially reverse multidrug resistance
through inhibition of the drug-efflux pump. EY-057 may activate
the alternative pathways to reverse MDR, since rhodamine
accumulation was not observed in MCF7/adr tre
ated with EY-057. Enhancement of apoptosis in adriamycin-
treated MCF7/adr cells is a common step for DQ-150 and EY-057
to achieve drug resistance reversal. Our study may create a
novel group of anticancer drug sensitizers in breast cancer.
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