Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer.
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.
Lin
Chi-Iou
CI
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Whang
Edward E
EE
Donner
David B
DB
Jiang
Xiaofeng
X
Price
Brendan D
BD
Carothers
Adelaide M
AM
Delaine
Tamara
T
Leffler
Hakon
H
Nilsson
Ulf J
UJ
Nose
Vania
V
Moore
Francis D
FD
Ruan
Daniel T
DT
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
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