Mechanism of Action Magnifier – 2016 Desk Reference
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 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 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
- 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.
- Farydak [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
- Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5:981-989.
- 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.
- 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.
Phosphatidylserine, an Immune-Modulating Checkpoint, Ushers in the Next Wave of Immuno-Oncology Targets
The immune system recognizes and is poised to eliminate cancer but is held in check by a plethora of inhibitory pathways that regulate cellular immune responses.1 These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during antimicrobial immune responses, can be co-opted by cancer to evade [ Read More ]
In my medical oncology practice at Johns Hopkins, I see approximately 4 patients with nonmetastatic NSCLC per week. Most of these patients are referrals from either pulmonary medicine or thoracic surgery. A patient with early stage disease initially sees a pulmonologist for diagnosis and may then be referred to a thoracic surgeon. The thoracic surgeon may refer the patient to us in medical oncology if there is an indication to enroll the patient in a clinical trial or for systemic therapy. In a community oncology practice, patients tend to go to surgery first and are then referred to the medical oncologist for adjuvant chemotherapy. In academic centers, it is more common for patients to be seen in a multidisciplinary setting.