The transition from a
chemotherapy-responsive
cancer to a
chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many
anticancer agents. We recently showed that a Forkhead box-containing
protein of the O subfamily 1 (FoxO1) is a key regulator of MDR1 gene transcription. Because nuclear localization of FoxO1 is regulated by silent information regulator two ortholog 1 (
SIRT1) deacetylase, we wondered whether
SIRT1 dominates MDR1 gene expression in
breast cancer cells. Overexpression of
SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1.
Protein expression of MDR1 and gene transcriptional activity were also up-regulated by
SIRT1 overexpression. In addition,
SIRT1 inhibition reduced both nuclear FoxO1 levels and MDR1 expression in
doxorubicin-resistant
breast cancer cells (MCF-7/ADR) cells. A potent
SIRT1 inhibitor,
amurensin G (from Vitis amurensis), was identified by screening
plant extracts and bioassay-guided fractionation. The compound suppressed FoxO1 activity and MDR1 expression in MCF-7/ADR cells. Moreover, pretreatment of MCF-7/ADR cells with 1 μg/ml
amurensin G for 24 h increased cellular uptake of
doxorubicin and restored the responsiveness of MCF-7/ADR cells to
doxorubicin. In xenograft studies, injection of 10 mg/kg i.p.
amurensin G substantially restored the ability of
doxorubicin to inhibit MCF-7/ADR-induced
tumor growth. These results suggest that
SIRT1 is a potential therapeutic target of MDR1-mediated chemoresistance and that it may be possible to develop
amurensin G as a useful agent for chemoresistance reversal.