by Margaret Brown | Mar 19 2012
Introduction: Inhibition of HDAC
Of the 18 isoforms of the histone deacetylase enzyme the class one and class two proteins are the most frequently found to be over expressed in tumor tissue [1;2]. The activity of the HDAC enzyme is to remove an acetyl group from a target protein which induces a conformational change so that further protein binding is induced or inhibited. The signal begins in the cellular cytosole and is transmitted to the nucleus. This signaling transfer results eventually in the regulation of a cellular growth activity, be that life or death! The class 1 & 2 enzymes function by binding their target protein to a binding domain which has a zinc atom as a functional part. This zinc atom catalysis the deacetylation process and is the target of inhibition for most known HDAC inhibitors. [3;4]
Panobinostat is a small molecule inhibitor that has demonstrated pan-HDAC activity with known IC50’s against HDAC’s 1-9 ranging between 3 – 61 nM (note HDAC 8 is the exception which has a IC50 of 248 nM). Panobinostat has demonstrated during the initial screening the ability to inhibit tumor cell proliferation and to induce apoptosis in cells of breast cancer and T cell lymphoma [5;6].
Panobinostat: Properties and Availability
Developed by the pharmaceutical company Novartis it has been on the market for a relatively short time. Prior to being known as Panobinostat it was researched under the code name LBH589. Literature reports that Panobinostat structure is based on a hydroxycinnamamide core wit substituted methlindolyl side chains . To determine that activity of pinobinostat it was screened against a panel of kinases, it demonstrated activity for HDAC enzymes but literature does not specify which HDAC’s it has activity against, reported Panobinostat IC50 against purified HDAC is listed as ± 50 nM. Panobinostat stability is recorded on the MSDS for its powered form, this is relatively stable if kept at -20°C, and again the recommended expiration date is listed as 2 years. In buffer solutions Panobinostat solubility is very poor but it will dissolve in both DMSO and ethanol to maximal concentrations of 200 and 5 mg/ml respectively. Researchers can buy Panobinostat from a variety of Panobinostat suppliers although Panobinostat cost is dependent on the supplier. Panobinostat price of a 5 mg vial range quite dramatically from $42 up to $895; researchers are advised to shop very carefully for this product.
Panobinostat: Preclinical investigations and clinical status
Panobinostat is a pan-HDAC inhibitor and is being investigated both pre-clinically and clinically against a variety of different tumor types. It is reported that the activity of Panobinostat against various growth processes occurs at concentration well below the known toxic concentration. Activity has been demonstrated in vasculogenesis, phosphorylation, endothelial tube formation and inhibition of the AKt pathway . In combination with TRAIL (a known chemotherapy agent) Panobinostat has been demonstrated to increase the sensitivity of the cell lines towards TRAIL induced apoptosis . Interestingly the cell lines respond most significantly were derived from pancreatic and mesothelioma cancers. In a separate study Panobinostat is reported to have induced conformational changes in protein structure which induced cell death, the cell lines used here were derived from breast cancer . In relation to the heat shock protein (HSP90) HDAC inhibition was demonstrated in lung cancer cell lines to induce acetylation which resulted in EGFR depletion / apoptosis . In a study continuing the investigation into the relationship of Panobinostat with HSP90 proteins it was observed that significant activity in AML and CML cell lines resulted from the combinational use of HSP90 inhibitors . Further combinational investigations showed significant anti-tumor effects with rapamycin in xenografts models. In prostate, renal cell carcinoma and endothelial cells the same combination induced apoptotic effects .
Clinically Panobinostat has been trialed at phase I with acute myeloid leukemia patients, toxicity was determined to be minimal while the anti tumor activity was observable . In direct contrast a combination with gemcitabine demonstrated significant toxicity in patient with various solid tumors but patients did respond to treatment with a number of sable diseases [15-17]. In a separate comparison study with docetaxel it was demonstrated that Panobinostat was as a single therapy compared to combination with docetaxel . In recurrent glioma’s Panobinostat demonstrated anti-tumor activity registering an 80% stable disease / partial response rate prompting phase II trials to be initiated .
Novartis reports that Panobinostat has reached phase II status and is undergoing testing in a multitude of tumor types such as Hodgkin’s lymphoma, acute myeloid leukemia, myelodysplastic and multiple myeloid. Data for these studies is not available at this time but Novartis indicates that phase III trials will go ahead in relapsed multiple myeloid and in Hodgkin’s lymphoma.
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