title: Ritterostatin GN1N, a Cephalostatin-Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78.
abstract: Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine-cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN1N, a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P. O. Box 210207, Tuscon, AZ, 85721, USA.
authors.forename: Andrew J
authors.identifier: 0000-0002-2932-4514
authors.initials: AJ
authors.lastname: Ambrose
authors.affiliation: Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.
authors.forename: Evelyne A
authors.initials: EA
authors.lastname: Santos
authors.affiliation: Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.|Instituto do Mar, Universidade Federal de São Paulo, Santos, SP, 11.070-100, Brazil.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Jimenez
authors.affiliation: Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.
authors.forename: Danilo D
authors.initials: DD
authors.lastname: Rocha
authors.affiliation: Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.
authors.forename: Diego V
authors.initials: DV
authors.lastname: Wilke
authors.affiliation: Waitt Advanced Biophotonics Center, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Beuzer
authors.affiliation: Waitt Advanced Biophotonics Center, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Axelrod
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.|Present address: On Target Laboratories, 1281 Win Hentschel Boulevard, West Lafayette, IN, 47907, USA.
authors.forename: Ananda
authors.identifier: 0000-0003-2669-8665
authors.initials: A
authors.lastname: Kumar Kanduluru
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Fuchs
authors.affiliation: Waitt Advanced Biophotonics Center, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Hu
authors.identifier: 0000-0002-7096-2905
authors.initials: H
authors.lastname: Cang
authors.affiliation: Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, 60.430-270, Brazil.|Departamento de Farmacologia, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Letícia V
authors.identifier: 0000-0003-1861-5153
authors.initials: LV
authors.lastname: Costa-Lotufo
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P. O. Box 210207, Tuscon, AZ, 85721, USA.
authors.forename: Eli
authors.identifier: 0000-0002-6310-1664
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Xenobe Research Institute, P. O. Box 3052, San Diego, CA, 92163-1052, USA.
authors.forename: James J
authors.identifier: 0000-0001-6500-4107
authors.initials: JJ
authors.lastname: La Clair
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003374:Coumarins / Q000737:chemistry*; D016503:Drug Delivery Systems; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015335:Molecular Probes; D015394:Molecular Structure; D010619:Phenazines / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D013256:Steroids / Q000737:chemistry*
chemical_list: D003374:Coumarins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D015335:Molecular Probes; D010619:Phenazines; D011719:Pyrazines; D013256:Steroids; C000621305:ritterostatin GN1N
keywords: GRP78; cephalostatin; drug discovery; natural products; ritterazine