title: Identification of Doxorubicin as an Inhibitor of the IRE1α-XBP1 Axis of the Unfolded Protein Response.
abstract: Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α-XBP1-dependent tumors such as MM.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Lynch
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Liedtke
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bam
authors.affiliation: Department of Biological Sciences, University of California, San Diego, CA 92093 USA.
authors.forename: Arvin B
authors.initials: AB
authors.lastname: Tam
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Zhifen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Muthuraman
authors.initials: M
authors.lastname: Alagappan
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Parveen
authors.initials: P
authors.lastname: Abidi
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.affiliation: Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210 USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
authors.affiliation: Department of Biological Sciences, University of California, San Diego, CA 92093 USA.
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004722:Endoribonucleases / Q000378:metabolism*; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*
chemical_list: D059003:Topoisomerase Inhibitors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D005047:Etoposide; D004317:Doxorubicin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases