title: Induction of cell cycle arrest and apoptosis with downregulation of Hsp90 client proteins and histone modification by 4β-hydroxywithanolide E isolated from Physalis peruviana.
abstract: Physalis peruviana (Solanaceae) is used for culinary and medicinal purposes. We currently report withanolides, isolated from P. peruviana, inhibit the growth of colon cancer monolayer and spheroid cultures. A detailed mechanistic evaluation was performed with 4β-hydroxywithanolide E (4HWE).
  
  
  
  Treatment of HT-29 cells with low concentrations of 4HWE inhibited growth while enhancing levels of p21(Waf1/Cip1) and reducing levels of several cell cycle-related proteins. Apoptosis was induced at higher concentrations. In addition, 4HWE treatment downregulated the levels of Hsp90 client proteins. Nuclear sirtuin 1 (SIRT1) was increased and histone H3 acetylated at lysine 9 was decreased. An additional consequence of SIRT1 elevation in the nucleus may be inhibition of c-Jun activity. The expression of 21 genes was altered, including downregulation of PTGS2, and this correlated with reduced protein levels of cyclooxygenase-2 (COX-2). Overall, efficacious induction of G0/G1 cell cycle arrest at low concentrations, and induction of apoptosis at higher concentrations are interesting 4HWE-mediated phenomena that are accompanied by a complex array of molecular events.
  
  
  
  Considering the worldwide prevalence of colon cancer, and the unique mode of action mediated by 4HWE, it is reasonable to investigate additional mechanistic details and the potential utility of this compound.
authors.affiliation: Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.|Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.
authors.forename: Mayuramas
authors.initials: M
authors.lastname: Sang-Ngern
authors.affiliation: Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.
authors.forename: Leng Chee
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.|Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D042421:Histone Code / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D032321:Physalis / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*
chemical_list: C554450:4-hydroxywithanolide E; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D010936:Plant Extracts; D054358:Withanolides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Apoptosis; Cell cycle arrest; Colorectal cancer cell; Cyclooxygenase-2; Sirtuin 1; c-myc