Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1

TY - JOUR

T1 - Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1

AU - Oh, Won Keun

AU - Cho, Kyoung Bin

AU - Hien, Tran Thi

AU - Kim, Tae Hyung

AU - Kim, Hyung Sik

AU - Dao, Trong Tuan

AU - Han, Hyo-Kyung

AU - Kwon, Seong-Min

AU - Ahn, Sang-Gun

AU - Yoon, Jung-Hoon

AU - Kim, Tae Hyun

AU - Kim, Yoon Gyoon

AU - Kang, Keon Wook

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

KW - Animals

KW - Antibiotics, Antineoplastic

KW - Cell Line, Tumor

KW - Dibenzocycloheptenes

KW - Down-Regulation

KW - Doxorubicin

KW - Drug Resistance, Neoplasm

KW - Drug Screening Assays, Antitumor

KW - Drug Synergism

KW - Female

KW - Forkhead Transcription Factors

KW - Humans

KW - Methanol

KW - Mice

KW - Mice, Nude

KW - Neoplasm Transplantation

KW - P-Glycoprotein

KW - Plant Extracts

KW - Resorcinols

KW - Sirtuin 1

KW - Stilbenes

KW - Structure-Activity Relationship

KW - Transplantation, Heterologous

KW - Vitis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1124/mol.110.065961

DO - 10.1124/mol.110.065961

M3 - Journal article

C2 - 20713551

SN - 0026-895X

VL - 78

SP - 855

EP - 864

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 5

ER -