Amurensin G, a Potent Natural SIRT1 Inhibitor, Rescues Doxorubicin Responsiveness via Down-Regulation of Multidrug Resistance 1

Abstract

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.

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

“…We have previously shown that phosphorylated FOXO1 is overexpressed in gastric cancer specimens and that FOXO1 inactivation is related to better prognosis of gastric cancer patients [18]. Although FOXO proteins, especially FOXO1 and FOXO3, have been reported to be related to chemoresistance in various cancer cells [8][9][10][19][20][21], their involvement in chemoresistance of gastric cancer cells has not been reported. In the present study, we used two gastric cancer cell lines, MKN45 and SNU-601, with constitutive FOXO1 expression and found that CDDP treatment increased the levels of FOXO1 protein expression and activation.…”

“…The function of FOXO1 in chemoresistance in cancer cells has been evaluated in in vitro studies [8][9][10]. FOXO1 increased doxorubicin resistance in breast cancer cells [8] and paclitaxel resistance in ovarian cancer cells [9], whereas it decreased CDDP resistance in ovarian cancer cells [10].…”

“…FOXO1 increased doxorubicin resistance in breast cancer cells [8] and paclitaxel resistance in ovarian cancer cells [9], whereas it decreased CDDP resistance in ovarian cancer cells [10]. Thus, the effect of FOXO1 on the chemoresistance of cancer cells may differ according to the drug and cell type investigated.…”

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

“…In cancer cells, FOXO1 downregulation is associated with cancer progression and resistance to chemotherapy [5][6][7], and its function is inhibited by the phosphatidylinositol 3-kinase-Akt-FOXO1 axis [8]. Therefore, the FOXO1 regulating mechanism has been speculated to be a promising target to overcome refractory GC.…”

BCRP Expression in VX2 Rabbit Liver Tumours and its Effects on Tumour Recurrence, Metastasis and Treatment Tolerability

“…Researches find that, multidrug resistance (MDR) is the most important cellular defense mechanism for malignant tumor to drug attack (Oh et al, 2010), and an important reason for treatment failure and tumor recurrence and metastasis, which is a problem urgent to be solved in clinic. It is cross-resistance phenomenon of tumor cells to a variety of unrelated drugs with different molecular structures, cellular targets and action mechanisms.…”