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Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 concentrations between 4 and 31 nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades. Combination therapy with carboplatin elicited rapid tumor cell kill and effectively restrained anchorage-independent clonogenic survival to a considerably greater extent over either monotherapy. The administration of carboplatin and panobinostat at clinically relevant doses to NOD-SCID xenograft mice drastically stalled disease progression by 92% as compared with negative control (P = .0026), but significant less as 28% and 54% with either carboplatin (P = .220) or panobinostat (P = .017) alone. These data demonstrate that panobinostat has strong anti-NSCLC activity and chemosensitizes tumors to carboplatin, thus justifying further evaluation of this combination approach in clinical trials.
This article was published in the following journal.
Name: Cancer letters
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Phenomenon of cell-mediated immunity measured by in vitro inhibition of the migration or phagocytosis of antigen-stimulated LEUKOCYTES or MACROPHAGES. Specific CELL MIGRATION ASSAYS have been developed to estimate levels of migration inhibitory factors, immune reactivity against tumor-associated antigens, and immunosuppressive effects of infectious microorganisms.
A cell adhesion molecule that contains extracellular immunoglobulin V and C2 domains. It mediates homophilic and heterophilic cell-cell adhesion independently of calcium, and acts as a tumor suppressor in NON-SMALL-CELL LUNG CANCER (NSCLC) cells. Its interaction with NATURAL KILLER CELLS is important for their cytotoxicity and its expression by MAST CELLS plays a role in their interaction with neurons; it may also function in synapse assembly, nerve growth and differentiation.
A fungal metabolite that blocks cytoplasmic cleavage by blocking formation of contractile microfilament structures resulting in multinucleated cell formation, reversible inhibition of cell movement, and the induction of cellular extrusion. Additional reported effects include the inhibition of actin polymerization, DNA synthesis, sperm motility, glucose transport, thyroid secretion, and growth hormone release.
An organoplatinum compound that possesses antineoplastic activity.
A form of highly malignant lung cancer that is composed of small ovoid cells (SMALL CELL CARCINOMA).
GILOTRIF (afatinib) is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L8...
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