title: GSK-3 inhibition overcomes chemoresistance in human breast cancer.
abstract: Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine protein kinase, is an emerging therapeutic target in the treatment of human breast cancer. In this study, we demonstrate that the pharmacological inhibition of GSK-3 by two novel small molecule GSK-3 inhibitors, 9-ING-41 and 9-ING-87, reduced the viability of breast cancer cells but had little effect on non-tumorigenic cell growth. Moreover, treatment with 9-ING-41 enhanced the antitumor effect of irinotecan (CPT-11) against breast cancer cells in vitro. We next established two patient-derived xenograft tumor models (BC-1 and BC-2) from metastatic pleural effusions obtained from patients with progressive, chemorefractory breast cancer and demonstrated that 9-ING-41 also potentiated the effect of the chemotherapeutic drug CPT-11 in vivo, leading to regression of established BC-1 and BC-2 tumors in mice. Our results suggest that the inhibition of GSK-3 is a promising therapeutic approach to overcome chemoresistance in human breast cancer, and identify the GSK-3 inhibitor 9-ING-41 as a candidate targeted agent for metastatic breast cancer therapy.
authors.affiliation: Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 2170 Campus Drive, Evanston, IL 60208, USA; Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ugolkov
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Gaisina
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Institute of Genomics and Systems Biology, University of Chicago, 900 East 57th Street, KCBD 10100A, Chicago, IL 60637, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kozikowski
authors.affiliation: Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA.
authors.forename: Sarika
authors.initials: S
authors.lastname: Jain
authors.affiliation: Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Halloran
authors.affiliation: Department of Medicine, University of Wisconin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
authors.affiliation: Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 2170 Campus Drive, Evanston, IL 60208, USA; Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Searle Building 8-510, 320 East Superior Street, Chicago, IL 60611, USA. Electronic address: a-mazar@northwestern.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000077146:Irinotecan; D008301:Maleimides / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595152:3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-f)indol-7-yl)-pyrrole-2,5-dione; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D000077146:Irinotecan; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D002166:Camptothecin
keywords: 9-ING-41; Breast cancer; Chemoresistance; Drug development; GSK-3