Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1.
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.
Oh
Won Keun
WK
College of Pharmacy, Chosun University, Dong-gu, Gwangju, South Korea.
Cho
Kyoung Bin
KB
Hien
Tran Thi
TT
Kim
Tae Hyung
TH
Kim
Hyung Sik
HS
Dao
Trong Tuan
TT
Han
Hyo-Kyung
HK
Kwon
Seong-Min
SM
Ahn
Sang-Gun
SG
Yoon
Jung-Hoon
JH
Kim
Tae Hyun
TH
Kim
Yoon Gyoon
YG
Kang
Keon Wook
KW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D000432:Methanol; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010936:Plant Extracts / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D027843:Vitis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003986:Dibenzocycloheptenes; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D010936:Plant Extracts; D012118:Resorcinols; D013267:Stilbenes; C553921:amurensin G; D004317:Doxorubicin; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000432:Methanol