Mechanism of Action Magnifier – 2016 Desk Reference

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Panobinostat: a Histone Deacetylase Inhibitor

In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone ace­tyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins.2 Removal of these acetyl groups results in tightly coiled DNA, which prevents cells from making proteins or dividing.1

HDACs


HDACs control several vital cellular processes, including the expression of some genes.3 In cancer, HDACs are expressed differently between cells, resulting in gene expression changes that can favor a tumor’s ability to multiply, to avoid apoptosis, or to become resistant to chemotherapy.3-5

Panobinostat

Panobinostat is an HDAC inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations.2 Inhibition of HDAC activity by panobinostat results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation.2 In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells.2 Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat.2 Panobinostat shows more cytotoxicity toward tumor cells than toward normal cells.2

References

  1. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:1210-1216.
  2. Farydak [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
  3. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5:981-989.
  4. Buggy JJ, Cao ZA, Bass KE, et al. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther. 2006;5:1309-1317.
  5. Stiborová M, Eckschlager T, Poljaková J, et al. The synergistic effects of DNA-targeted chemotherapeutics and histone deacetylase inhibitors as therapeutic strategies for cancer treatment. Curr Med Chem. 2012;19:4218-4238.
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Cancers develop when mutations in critical genes alter cells’ ability to proliferate, differentiate, and die. One of these critical genes is the BRAF gene. Mutations in BRAF result in overactive, or oncogenic, BRAF protein, which ultimately enhances cell proliferation and survival.1 Because BRAF mutations are present in more than half [ Read More ]