title: Inhibition of SIRT1 signaling sensitizes the antitumor activity of silybin against human lung adenocarcinoma cells in vitro and in vivo.
abstract: Although silybin, a natural flavonolignan, has been shown to exhibit potent antitumor activities against various types of cancers, including lung cancer, the molecular mechanisms behind these activities remain unclear. Silent information regulator 1 (SIRT1) is a conserved NAD(+)-dependent deacetylase that has been implicated in the modulation of transcriptional silencing and cell survival. Furthermore, it plays a key role in carcinogenesis through the deacetylation of important regulatory proteins, including p53. In this study, we investigated the antitumor activity of silybin towards human lung adenocarcinoma cells in vitro and in vivo and explored the role of the SIRT1 signaling pathway in this process. Silybin treatment resulted in a dose- and time-dependent decrease in lung adenocarcinoma A549 cell viability. In addition, silybin exhibited strong antitumor activity illustrated by reductions in tumor cell adhesion, migratory capability, and glutathione levels and by increased apoptotic indices and reactive oxygen species levels. Silybin treatment also downregulated SIRT1 and upregulated p53 acetylation. SIRT1 siRNA (in vitro) or cambinol (a known SIRT1 inhibitor used for in vivo studies) further enhanced the antitumor activity of silybin. In summary, silybin is a potent inhibitor of lung adenocarcinoma cell growth that interferes with SIRT1 signaling, and this inhibition is a novel mechanism of silybin action that may be used for therapeutic intervention in lung adenocarcinoma treatment.
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital of General Hospital of PLA, Beijing, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital;
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an; and.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Yan
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital;
authors.forename: Yingtong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital;
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital; wenshengchen210@126.com weixunduan210@126.com.
authors.forename: Weixun
authors.initials: W
authors.lastname: Duan
authors.affiliation: Authors' Affiliations: Department of Cardiovascular Surgery, Xijing Hospital; wenshengchen210@126.com weixunduan210@126.com.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012838:Silymarin; D000077385:Silybin; D053148:Caspase 3; D056564:Sirtuin 1; D005978:Glutathione