3,3',5-Triiodo-L-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy.
The pancreatic adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression, and profound resistance to actual treatments, including chemotherapy and radiotherapy. At the moment, surgical resection provides the best possibility for long-term survival, but is feasible only in the minority of patients, when advanced disease chemotherapy is considered, although the effects are modest. Several studies have shown that thyroid hormone, 3,3',5-triiodo-l-thyronine (T(3)) is able to promote or inhibit cell proliferation in a cell type-dependent manner. The aim of the present study is to investigate the ability of T(3) to reduce the cell growth of the human pancreatic duct cell lines chosen, and to increase the effect of chemotherapeutic drugs at conventional concentrations. Three human cell lines hPANC-1, Capan1, and HPAC have been used as experimental models to investigate the T(3) effects on pancreatic adenocarcinoma cell proliferation. The hPANC-1 and Capan1 cell proliferation was significantly reduced, while the hormone treatment was ineffective for HPAC cells. The T(3)-dependent cell growth inhibition was also confirmed by fluorescent activated cell sorting analysis and by cell cycle-related molecule analysis. A synergic effect of T(3) and chemotherapy was demonstrated by cell kinetic experiments performed at different times and by the traditional isobologram method. We have showed that thyroid hormone T(3) and its combination with low doses of gemcitabine (dFdCyd) and cisplatin (DDP) is able to potentiate the cytotoxic action of these chemotherapic drugs. Treatment with 5-fluorouracil was, instead, largely ineffective. In conclusion, our data support the hypothesis that T(3) and its combination with dFdCyd and DDP may act in a synergic way on adenopancreatic ductal cells.
Michienzi
Simona
S
Chair of Endocrinology, II Faculty of Medicine, University La Sapienza, Rome, Italy.
Bucci
Barbara
B
Verga Falzacappa
Cecilia
C
Patriarca
Valentina
V
Stigliano
Antonio
A
Panacchia
Laura
L
Brunetti
Ercole
E
Toscano
Vincenzo
V
Misiti
Silvia
S
D000963:Antimetabolites / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D019938:Cyclin D1 / Q000032:analysis; D056742:Cyclin D2; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D016213:Cyclins / Q000032:analysis; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011988:Receptors, Thyroid Hormone / Q000032:analysis; D014284:Triiodothyronine / Q000627:therapeutic use*; D054462:p21-Activated Kinases; D000093542:Gemcitabine
D000963:Antimetabolites; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D003841:Deoxycytidine; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine