Profile of panobinostat and its potential for treatment in solid tumors: an update

Abstract

The histone deacetylase (HDAC) inhibitors have emerged as novel therapies for cancer. Panobinostat (LBH 589, Novartis Pharmaceuticals) is a pan-deacetylase inhibitor that is being evaluated in both intravenous and oral formulations across multiple tumor types. Comparable to the other HDACs, panobinostat leads to hyperacetylation of histones and other intracellular proteins, allowing for the expression of otherwise repressed genes, leading to inhibition of cellular proliferation and induction of apoptosis in malignant cells. Panobinostat, analogous to other HDAC inhibitors, also induces apoptosis by directly activating cellular death receptor pathways. Preclinical data suggests that panobinostat has inhibitory activity at nanomolar concentrations and appears to be the most potent clinically available HDAC inhibitor. Here we review the current status of panobinostat and discuss its role in the treatment of solid tumors.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

“…HDAC inhibitors induce apoptosis, cell-cycle arrest, and terminal differentiation in a variety of human tumors and, while currently only clinically licensed for hematological malignancies, show promise in solid tumors, including NSCLC (33). Three class I HDAC inhibitors-JNJ-26481585 (34,35), panobinostat, and vorinostat-were tested in the panel of patient-derived NSCLC specimens.…”

Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis

“…HDACs are classified into four groups: class I (HDAC1, HDAC2, HDAC3 and HDAC8) are located primarily in the nuclei; class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10) are located in the cytoplasm but can shuttle to the nucleus; class III are NAD + -dependent enzymes and known as the sirtuins; class IV is represented by HDAC11 only 9. Class I, II and IV HDACs are Zn 2+ -dependent enzymes, and can thus be efficiently inhibited by chelating agents such as the hydroxamic acids vorinostat (SAHA) and panobinostat (LBH589) 9 11 12. Importantly, these HDAC inhibitors (HDACi) have been reported as successful anticancer agents as they induce cell cycle arrest and apoptosis in cancer cells by increasing the acetylation status of chromatin and other non-histone proteins 9 11 12…”

“…Class I, II and IV HDACs are Zn 2+ -dependent enzymes, and can thus be efficiently inhibited by chelating agents such as the hydroxamic acids vorinostat (SAHA) and panobinostat (LBH589) 9 11 12. Importantly, these HDAC inhibitors (HDACi) have been reported as successful anticancer agents as they induce cell cycle arrest and apoptosis in cancer cells by increasing the acetylation status of chromatin and other non-histone proteins 9 11 12…”

Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies

“…Romidepsin (depsipeptide, FK228, Istodax ™ ), a prodrug whose disulphide bond must be reduced to yield the active form, is also approved for peripheral T-cell lymphoma (PTCL) [60]. Further hydroxamic acid-based HDACIs, including panobinostat (LBH589) and belinostat (PXD101), are active in a wide range of hematologic malignancies and different solid tumors, as recently reviewed by Grassadonia et al [61] and Anne et al [62].…”