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, a/b 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 a-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.Anaplastic thyroid carcinoma (ATC), which accounts for 1% of thyroid tumors, is one of the most lethal malignancies, with a rapidly fatal clinical course.

The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

“…This finding is in contrast to the study by Gupta et al 11 in diffuse and large B-cell lymphoma in which panobinostat effectively inhibited mTORC1 and underlines the divergences that can occur between different cell lines. As previously reported in other cancer types, 22,23 panobinostat induced a cell-cycle arrest in G 2 /M in HL cell lines. Moreover, the combination of panobinostat with everolimus was also more effective to induce this cell-cycle arrest in G 2 /M than the use of panobinostat alone.…”

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

“…It was, in addition, reported to induce re-expression of previously silenced genes modulating thus the behaviour of cancer cells (35)(36)(37).…”

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

“…A total of 3 × 10 7 U266 cells in 100 μl of RPMI-1640 were mixed with the same volume of Matrigel (BD Biosciences), and the mixture was s.c. injected into the back of the mouse. Tumors were measured with calipers, and volumes were calculated using the formula α 2 × β × 0.5, where α is the shortest diameter and β is the diameter perpendicular to α, as described previously (64). When the diameter of the tumor reached 1.0 cm, treatment with vehicle, panobinostat, FK506, or both panobinostat and FK506 was initiated.…”