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: Maria Graziella Catalano, Mariateresa Pugliese, Eleonora Gargantini, Cristina Grange, Benedetta Bussolati, Sofia Asioli, Ornella Bosco, Roberta Poli, Alessandra Compagnone, Andrea Bandino, Franco Mainini, Nicoletta Fortunati, Giuseppe Boccuzzi
• Journal: International journal of cancer (Int J Cancer) Vol. 130 Issue 3 Pg. 694-704 (Feb 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21400508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Indoles
• Tubulin
• Panobinostat

Topics

• Acetylation (drug effects)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use, toxicity)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use, toxicity)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (pharmacology, therapeutic use, toxicity)
• Indoles
• Mice
• Mice, Nude
• Panobinostat
• Thyroid Carcinoma, Anaplastic
• Thyroid Neoplasms (drug therapy, genetics, metabolism)
• Tubulin (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays