title: Psammaplin A induces Sirtuin 1-dependent autophagic cell death in doxorubicin-resistant MCF-7/adr human breast cancer cells and xenografts.
abstract: BACKGROUND
  Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed.
  
  
  METHODS
  We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model.
  
  
  CONCLUSIONS
  PsA significantly inhibited MCF-7/adr cells proliferation in a concentration-dependent manner, with accumulation of cells in G2/M phase of the cell cycle. PsA significantly decreased SIRT1 enzyme activity and reduced expression of SIRT1 protein in the cultured cells with greater potency than sirtinol or salermide. Acetylation of p53, a putative target of SIRT1, increased significantly following PsA treatment. In addition, PsA markedly increased the expression levels of autophagy-related proteins. In support of this, it was found that PsA significantly increased the expression of damage-regulated autophagy modulator (DRAM), a p53-induced protein.
  
  
  CONCLUSIONS
  The results of this study suggest that PsA is sufficient to overcome multidrug-resistant cancer via SIRT1-mediated autophagy in MCF-7/adr breast cancer cells, indicating that PsA has therapeutic potential for clinical use.
authors.affiliation: Division of Toxicology, School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Hyuk Soon
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Division of Toxicology, School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Yoon Jong
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Research Institute, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Division of Toxicology, School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 440-746, Republic of Korea. Electronic address: hkims@skku.edu.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004220:Disulfides / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; C512709:DRAM1 protein, human; D004220:Disulfides; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C098378:psammaplin A; D014443:Tyrosine; D004317:Doxorubicin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Autophagy; Breast cancer; Doxorubicin; Drug-resistant; SIRT1