Antitumor activity of suberoylanilide hydroxamic acid against thyroid cancer cell lines in vitro and in vivo.
OBJECTIVE
The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), has multiple antitumor effects against a variety of human cancers.


METHODS
We treated several anaplastic and papillary thyroid cancer cell lines with SAHA to determine if it could inhibit the growth of these cells in vitro and in vivo.


RESULTS
SAHA effectively inhibited 50% clonal growth of the anaplastic thyroid cancer cell lines, ARO and FRO, and the papillary thyroid cancer cell line, BHP 7-13, at 1.3x10(-7) to 5x10(-7) mol/L, doses that are achievable in patients. In concert with growth inhibition, SAHA down-regulated the expression of cyclin D1 and up-regulated levels of p21WAF1. Annexin V and cleavage of poly(ADP)ribose polymerase were both increased by exposure of the thyroid cancer cells to SAHA. Expression of the death receptor 5 (DR5) gene was also increased by SAHA, but the combination of the DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with SAHA had little effect compared with SAHA alone. Of note, the combination of paclitaxel, doxorubicin, or paraplatin with SAHA enhanced cell killing of the thyroid cancer cells. In addition, murine studies showed that SAHA administered daily by i.p. injection at 100 mg/kg inhibited the growth of human thyroid tumor cells.


CONCLUSIONS
Our data indicate that SAHA is a plausible adjuvant therapy for thyroid cancers.
Luong
Quang T
QT
Department of Medicine and the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California 90048, USA. trong.luong@gmail.com
O'Kelly
James
J
Braunstein
Glenn D
GD
Hershman
Jerome M
JM
Koeffler
H Phillip
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016190:Carboplatin / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D017239:Paclitaxel / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; D000077337:Vorinostat; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel