title: Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer.
abstract: Although most patients with papillary thyroid cancer (PTC) have favorable outcomes, some have advanced PTC that is refractory to external beam radiation and systemic chemotherapy. Galectin-3 (Gal-3) is a beta-galactoside-binding protein with antiapoptotic activity that is consistently overexpressed in PTC. The purpose of this study is to determine if Gal-3 inhibition promotes apoptosis, chemosensitivity, and radiosensitivity in PTC. PTC cell lines (8505-C and TPC-1) and human ex vivo PTC were treated with a highly specific small molecule inhibitor of Gal-3 (Td131_1). Apoptotic activity was determined by flow cytometric analysis as well as caspase-3 and PARP cleavage. The minimum inhibitory concentrations of Td131_1 and doxorubicin were determined, and their combined effects were measured to test for synergistic activity. The effects of Td131_1 on radiosensitivity were determined by a clonogenic assay. Td131_1 promoted apoptosis, improved radiosensitivity, and synergistically enhanced chemosensitivity to doxorubicin in PTC cell lines. In PTC ex vivo, Td131_1 treatment alone induced the cleavage of caspase-3 and PARP. Td131_1 and doxorubicin together activated apoptosis in PTC ex vivo to a greater degree than their combined individual effects. Td131_1 activated apoptosis and had synergistic activity with doxorubicin in PTC. We conclude that Gal-3 targeted therapy is a promising therapeutic strategy for advanced PTC that is refractory to surgery and radioactive iodine therapy.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: David B
authors.initials: DB
authors.lastname: Donner
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Tamara
authors.initials: T
authors.lastname: Delaine
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
authors.forename: Vania
authors.initials: V
authors.lastname: Nose
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D005434:Flow Cytometry; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D013862:Thiogalactosides / Q000138:chemical synthesis / Q000627:therapeutic use; D013865:Thioglycosides / Q000138:chemical synthesis / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy
chemical_list: D037502:Galectin 3; D011838:Radiation-Sensitizing Agents; C546996:Td131-1 compound; D013862:Thiogalactosides; D013865:Thioglycosides; D004317:Doxorubicin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3