title: Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo.
abstract: Anaplastic thyroid carcinoma (ATC) has a rapidly fatal clinical course, being resistant to multimodal treatments. Microtubules, α/β tubulin heterodimers, are crucial in cell signaling, division and mitosis and are among the most successful targets for anticancer therapy. Panobinostat (LBH589) is a potent deacetylase inhibitor acting both on histones and nonhistonic proteins, including α-tubulin. In vitro LBH589, evaluated in three ATC cell lines (BHT-101, CAL-62 and 8305C), resulted in impairment of cell viability, inhibition of colony formation, cell cycle arrest and apoptosis induction. Mechanistically, we showed that LBH589 not only affected the expression of p21 and cyclin D1, but markedly determined microtubule stabilization as evidenced by tubulin acetylation and increased tubulin polymerization. In a SCID xenograft model implanted with CAL-62 cells, the cytotoxic properties of LBH589 were confirmed. The drug at the dose of 20 mg/kg significantly impaired tumor growth (final tumor volume 2.5-fold smaller than in untreated animals); at this dose, no relevant side effects were observed. In tumors of treated animals, a significant reduction of Ki67, which was negatively correlated with tubulin acetylation, was observed. Moreover, acetyl-tubulin levels negatively correlated with tumor volume at sacrifice, reinforcing the opinion that tubulin acetylation has a role in the inhibition of tumor growth. In conclusion, LBH589, acting on both histones and nonhistonic proteins in anaplastic thyroid cancer, appears to be a promising therapeutic agent for the treatment of this kind of cancer which is known not to respond to conventional therapy.
authors.affiliation: Department of Clinical Pathophysiology, University of Turin, Torino, Italy.
authors.forename: Maria Graziella
authors.initials: MG
authors.lastname: Catalano
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Pugliese
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gargantini
authors.forename: Cristina
authors.initials: C
authors.lastname: Grange
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
authors.forename: Sofia
authors.initials: S
authors.lastname: Asioli
authors.forename: Ornella
authors.initials: O
authors.lastname: Bosco
authors.forename: Roberta
authors.initials: R
authors.lastname: Poli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Compagnone
authors.forename: Andrea
authors.initials: A
authors.lastname: Bandino
authors.forename: Franco
authors.initials: F
authors.lastname: Mainini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Fortunati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Boccuzzi
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D007211:Indoles; D051379:Mice; D008819:Mice, Nude; D000077767:Panobinostat; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D014404:Tubulin; D000077767:Panobinostat