Wednesday, April 25, 2012


The disease cancer is associated with a number of modifications and alterations in various signaling pathways. Amongst the various intracellular pathways, MAPK pathway has been found to be commonly hyper-activated in many cases of cancers. The normal functioning of the MAPK pathway is required for many vital functions like proliferation of the cell, regulation of the cell cycle, migration of the cell from one point to another and development of new blood vessels from the older ones. This pathway sends the extracellular signals to the nucleus. The components of this pathway are involved in a cross talk with many other members who belong to other pathways. The hyper-activation of this pathway can be controlled with the help of certain inhibitors which can control the overstimulation of the kinases. SB590885 is one such inhibitor.


The MAPK pathway originates from Ras, which sends the signal for the activation of different splice variants of RAF.  The three different splice variants of Raf are Raf-1, A-Raf and B-Raf. These splice variants bind to the ras and as a result, the complex is recruited to the membrane. This involves the phosphorylation of many co factors. The signal from Raf gets transmitted down through MEK1/2 and ERK1/2. Specific inhibitors are being designed which can target different components of the pathway. Inhibitors which target MEK were U0126 and PD 098059. Amongst these U0126 blocked the AP-1 mediated transcription. CI-1040 is another inhibitor which has received clinical approval and it makes the heterotransplants sensitive to paclitaxel [1]. Similarly an inhibitor which inhibits the upstream kinase that is B-Raf kinase is SB-590885. It is derived from triarylimidazole and it is highly selective in its action [2]. The antitumor activity of docetaxel was further enhanced by MEK inhibitor AZD6244.


The cerebrovascular receptors such as 5-HT1B, AT1 and ETB were found to be significantly increased within the vessel walls of the ischemic region. The increased expression of these receptors enhances the damage to the tissues by impairing the blood flow. These receptors get activated through the MAPK pathway. SB-386023 helped in the study of these receptors as it specifically inhibits B-Raf. When the Braf kinase was inhibited the expression of the contractile receptors was hampered. Hence the tissue damage can be prevented by inhibiting the Raf kinase activity [3].


The solid tumors are generally enhanced through signaling factors which are stimulated by the growth factors. Some MEK inhibitors which act as MAPK inhibitors show a synergistic action with EGFR inhibitors. Mutations within the BRAF kinase are commonly associated with many kinds of cancers especially in case of melanomas. SB-590885 helped in the analysis of the role of MAPK pathway, especially B-Raf kinase for the growth of tumor. Colorectal cancers and melanomas are usually associated with mutation BRAF V600E; hence these cells lines were tested with SB590885. The concentration of SB-590885 which was just sufficient to inhibit ERK was enough to curtail the growth and proliferation of the tumor cells. This shows that mutation within BRAF plays a primary role in stimulating colorectal cancers and melanomas [4].


In a nut shell SB-590885 checks the growth of those cancers which contain mutated BRAF kinase. It has helped the scientists to study the role of MAPK within various cancers.


1. Friday BB and Adjei AA. Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy. Clin Cancer Res 2008 Jan 15; 14; 342.
2. Taklea AK, Brown MJB, et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorganic & Medicinal Chemistry Letters 2006 Jan 15; 16(2); 378-381.
3. Ahnstedt H, Säveland H, et al. Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway. BMC Neurosci 2011 Jan 11; 12:5.
4. King AJ, Patrick DR, et al. A novel, potent and selective small molecule inhibitor of B-Raf kinase, SB-590885, inhibits signal transduction and growth of cells bearing the B-Raf V600E mutation. Proc Amer Assoc Cancer Res 2005; 46.



HDACs are a group of enzymes which deacetylate the lysine residues within the histone proteins. A balance between the HDACs and HATs decides the transcription of gene. Many cancers are associated with the hyper-secretion of HDACs. In order to regulate the levels of HDACs and hence cancer, many chemical compounds are being synthesized which can act potential inhibitors of HDACs. Such screening of the chemical libraries led to the discovery of a novel anticancer agent which is Vorinostat. Structurally it is a hydroxamate derivative which has suberoylanilide substitution.


Valproate, FK228 and Vorinostat are small molecules which show antineoplastic activity by virtue of their tendency to inhibit HDACs. They commonly inhibit the growth and stimulate the process of apoptosis within the cancerous cells. The cancer cells (colon) were subjected to increasing doses of these compounds and clonogenic data was collected. This data showed that these cells developed at least two times more resistance to these inhibitors. The resistance so developed could not be reversed. The mechanism behind this development of resistance was analyzed and it was found that in case of resistance due to Vorinostat - G2/M checkpoint was deprived. The levels of p21 and p27 which act as inhibitors to the cell cycle were maintained at a constant level. The reasons behind this resistance were not -stimulated expression of HDAC3 and HDAC1 or decline in apoptosis nor due to the alterations in the expression of MDR. It was also found that the resistance developed due to these two agents was mild and was independent of MDR expression. Hence this combination of inhibitors can be used as chemotherapeutic agents [1].


Vorinostat is presently undergoing rigorous clinical trials to study its effects on telomerase. The expression of hTERT (telomerase reverse transcriptase enzymes within human beings) was analyzed after the administration of Vorinostat within lung cancer cell lines. Vorinostat down regulated the expression of hTERT through epigenetic regulation. The CpG islands within the promoter regions of the genome which are subjective methylation are demethylated by the action of Vorinostat. This inhibitor checks the synthesis of DNA methyltransferases like DNMT1 and DNMT3b. These results suggest that Vorinostat adopts a novel mechanism of treating cancer through suppression of the telomerase activity [2].


A translocation within a region of chromosome results into over- expression of cyclin D1. This in turn leads to a cancerous situation known as MCL (Mantle cell lymphoma). SAHA reduces the levels of cyclin D1 proteins after a constant exposure for 8 hours. It did not disturb the stability of protein or the mRNA levels of cyclin D1. Within the MCL cells SAHA decreased the pAkt and eIF4E-BP levels. It also reduced the levels of Rapamycin. As a result the binding activity of eIF4E at the cap site was also reduced. SAHA inhibits the PI3K pathway [3].


The treatment using SAHA is associated with many beneficial effects but it also leads to a significant bone loss. The bone loss is because SAHA decreases the formation of osteogenic colony and expression of osteoblastic genes [4].


1. Fedier A, Dedes KJ, et al. The histone deacetylase inhibitors suberoylanilide hydroxamic (Vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells. International Journal of Oncology 2007 Sept; 31(3): 633-641.
2. Li CT, Hsiao YM, et al. Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells. J Cell Biochem 2011 Oct; 112(10):3044-53.
3. Kawamata N, Chen J, and Koeffler PH. Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 2007 Oct 1; 110(7): 2667-2673.
4. McGee-Lawrence ME, McCleary-Wheeler AL, et al. Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. Bone 2011 May 1; 48(5): 1117-26.



An imbalance between HDACs and HATs regulates the levels of acetylation of the histone proteins and subsequent transcription of genes. If the HDAC levels are high the deacetylation of the lysine residues are promoted. This affects large number of intracellular functions like apoptosis, differentiation, cellular proliferation etc. In order to control the levels of HDACs scientists have designed HDAC inhibitors. Valproate is one among them.


Valproate was administered along with adriamycin on MUTZ-1 cell line and its effects on tumor suppression were analyzed. The growth of the tumor cells was discovered through flow cytometry and growth curve was drawn. The growth inhibition rates were analysed at various concentrations. Valproate alone was unable to stimulate the process of apoptosis but when it worked in combination with adriamycin the rate of apoptosis was found to be increased. This research showed that this combination of inhibitors was very effective in controlling myelodysplastic syndrome [1].


Neurodegenerative disorders like Alzheimer's disease are associated with loss in the neuronal tissues. The main reason behind the Neuritic plaques is the secretion of Aβ –protein. This protein is produced as an out come of the endoproteolytic cleavages of type 1 APP by the secretase enzyme (β- and γ- isoforms). In case of Alzheimer's disease this cleavage fails and it leads to the accumulation of Aβ protein. Valproic acid has been used in case of bipolar disorder. This inhibitor inhibits calcium, potassium and sodium channels within the membrane. It increases the transmission of γ-aminobutyric acid and activates the kinases which control the function of AP-1 protein. Valproic acid interferes with neurotrophic responses. It alters the activity of HDACs and GSK-3. It acts similar to trichostatin A in increasing the expression of β-catenin and hence regulating the Wnt pathway. The analysis of the neuronal function of HDAC inhibitors revealed that they promote synaptogenesis through acetylation of the histone proteins. This improves ones memory and learning capacity. In case of Alzheimer's disease, studies have shown that VPA controls the cleavage of APP via γ-secretase enzyme. This enzyme is in turn under the control of GSK-3β. In mice this inhibitor increased the memory hence suggesting that it can be an efficient antiamyloid therapy [2]. It can be used as an anticonvulsant and stimulator of the process of apoptosis and differentiation within cancerous cells. Clinical trials have been done in cases of myelodysplastic problem and myeloid leukemia. It was administered alone and in combination with inhibitors (which have all-trans retinoic acid structure). The combination of inhibitors synergistically improved the hematologic condition [3].

Multiple myeloma cells express VEGFR-1 protein under in vitro conditions. Upon administration of VPA the growth of these cells was inhibited in a dose dependent manner. Upon exposure for longer hours (48 hours) the rate of apoptosis was also found to be increased. The expression of VEGFR-1 was reduced after the administration of VPA [4].


VPA is a fatty acid (short chain in length) derivative. It shows significant positive effects on various cellular functions like proliferation, differentiation, immunogenicity and apoptosis.


1. Yu C, Chen BA, et al. [Sodium valproate synergizes adriamycin to inhibit proliferation and induce apoptosis in myelodysplastic syndrome cell line]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008 Jun; 16(3):555-60.
2. Qing H, He G, et al. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 2008 Nov 24; 205(12):2781-9.
3. Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer 2007 Sep 1; 110(5):943-54.
4. Dong XF, Song Q, et al. Histone deacetylase inhibitor valproic acid inhibits proliferation and induces apoptosis in KM3 cells via downregulating VEGF receptor. Neuro Endocrinol Lett 2007 Dec; 28(6):775-80.

Friday, April 6, 2012



Development of new blood vessels from the older ones or angiogenesis is a very crucial process required for the normal functioning of the body including growth and development. In fact in adults many vital processes like healing of wounds and reproduction essentially require angiogenesis for their completetion. However this process is also associated with some diseases like cancer. Number of factors has been identified as angiogenesis promoters like VEGF family members – VEGF- A, B, C and D. They are the components of the VEGF pathway, which plays a dominant role in tumor angiogenesis. Regorafenib acts on VEGF family members.


Due to an uncontrolled cell division during the tumor growth, the oxygen diffusion is limited. A condition of hypoxia is created which activates transcription factors like HIF (hypoxia-inducible factor). This in-turn activates VEGF family members and when they combine with proteolytic factors, they stimulate the development of new vasculature within the tumor area. If this angiogenesis process is arrested the oxygen supply to the tumor will be cut and as a result the growth of tumor will be controlled. Various tyrosine kinase inhibitors are being designed which act as second generation inhibitors of VEGFR. Tivozanib is a tyrosine kinase inhibitor which inhibits three VEGFRs at concentration ranging between 0.16 nM to 0.24 nM. It is being tested under phase I clinical trails. Axitinib inhibits all the members of VEGFR family at a lower concentration and is considered to be very efficient [1]. Regorafenib was also discovered for the same purpose and in the same lines [1].


Various angiogenesis inhibitors are being tested for their potential to control melanoma and spread or metastasis of cancers. According the present research the effective mechanism to control the process of angiogenesis, is through the use of monoclonal antibodies like bevacizumab or by developing receptor traps which bind to the VEGF ligands. Another mechanism is the use of tyrosine kinase inhibitors with targets the members of VEGF family. Use of monoclonal antibodies offers a cytotoxic chemotherapeutic measure to control angiogenesis. The tyrosine kinase inhibitors do not allow the tumor to grow beyond the size of 1-2 mm as they cutl the supply of oxygen [2].


Tyrosine kinase and VEGFR -2 both contain a homology domain 2 and they are very essential for the growth and development of tumors. Regorafenib inhibits the kinases within the endothelial regions and angiogenesis kinases like VEGFR1 and VEGFR3, PDGFR – β and FGFR1. The kinases which are oncogenic in nature are B-RAF, KIT and RET. Regorafenib controls the levels of these kinases. MRI imaging studies were used to study the antiangiogenic effects. Within rats the process of extravasation was controlled. This inhibitor controlled the growth of tumor in a dose dependent manner. Regorafenib is well tolerated and does not cause adverse toxic side effects [3]. After undergoing clinical testing under phase I, it was found that Regorafenib is well tolerated at a concentration of 60 mg under physiological conditions. It was safe and inhibited all the angiogenic kinases.


Regorafenib is a second generation angiogenesis inhibitor which targets multiple kinases. It controls the growth of tumors by cutting the supply of oxygen.


1. Bhargava P and Robinson MO. Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status. Curr Oncol Rep 2011 April; 13(2): 103–111.
2. Corrie PG. Targeting angiogenesis in melanoma: prospects for the future. Ther Adv Med Oncol 2010 November; 2(6): 367–380.
3. Wilhelm SM, Dumas J, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011 Jul 1; 129(1):245-55
4. Hedbom S, Steinbild S, et al. Phase I study of BAY 73-4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 2007; 25(18S); 3593.



The activation of MAPK pathway is largely associated with multiple cancer cases. Amongst the various components of the MAPK pathway, the oncogenic mutations within RAS and BRAF affect the downstream kinases, during the course of clinical and preclinical development. The second generation BRAFV600E selective inhibitor – PLX-4032 was initially found to be highly efficient. This later led to the discovery of RAF265 on the same grounds.


Point mutations (somatic in nature) within the BRAF gene, are seen mostly in the cases of thyroid and colorectal cancers. These mutations are seen within the exon 11 and exon 15, of the kinase domain. A mutation which replaces the Val residue with Glu is most commonly seen in at least 90% cases. As a result the P-loop fails to interact with the activation section. This makes the kinase enzyme inactive. Sorafenib was the first FDA approved inhibitor of RAF kinase. Further search for the discovery of RAF selective inhibitors led to the discovery of PLX -4032, XL281 and finally RAF265. All the three different splice variants of RAF are inhibited by RAF265. Due to its inhibitory effects on VEGFR-2, it also acted as an angiogenesis inhibitor [1].


Two important pathways (PI3K and MAPK pathways) are stimulated by growth factors and these pathways play a vital role in intracellular functions like proliferation and survival. The transcription factors involved in the vital cellular functions are regulated by these pathways. Within the MAPK pathway, Ras molecule is very important as it regulates the expression of several nuclear proteins. Alterations in the PI3K pathway and KRAS mutations are associated with immortalization and proliferation of cells. They also offer resistance to various chemotherapeutic agents. Hence an effective inhibition of these two pathways proved to be an efficient mechanism to check the growth of cancer. RAF265 is an efficient inhibitor of RAF/VEGFR2 and Everolimus is a rapamycin inhibitor within mammals. Different cell lines showing KRAS, BRAF and PIK3CA mutations were taken and tested with these inhibitors individually. Everolimus inhibited the down-stream targets of mTOR in all the cell lines and proved to be anti-tumorous under both in vitro and in vivo conditions. RAF265 showed its action in only those cell lines which showed a mutation within the BRAF. When these inhibitors were applied in combination, the phosphorylation levels of S6, AKT and 4EBP1 were found to be decreased under in vitro conditions within HCT116 cells. The action of RAF265 was further enhanced by Everolimus within few cell lines like HCT116 and H460. However this combination did not work well in the following cell lines MDAMB231 and A549. These results suggest that a combination of RAF265 and Everolimus deregulates RAS activated MAPK and PI3K pathway. The cross inhibition of S6 and 4EBP1 may be the underlying mechanism behind this [2].

The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

When PRKD3 was blocked the activity of RAF265 was enhanced. This prevents the activation of the MAPK pathway again. As a result apoptosis is stimulated and cell cycle gets halted [3]. When the MAPK pathway is blocked by Raf265, the sensitivity towards TRAIL was enhanced within insulinoma cells. Within the TRAIL sensitive cells the levels of Bcl2 were found to be reduced [4].


In summary RAF265 shows a specific action against mutation within BRAF. It stimulates the process of apoptosis by sensitizing the cells to TRAIL.
1. Pratilas CA and Solit DB. Targeting the Mitogen-Activated Protein Kinase Pathway: Physiological Feedback and Drug Response. Clin Cancer Res 2010 May 14; 16: 3329-3334.
2. Mordant P, Loriot Y, et al. Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination. Mol Cancer Ther 2010 Feb; 9(2):358-68.
3. Chen J, Shen Q, et al. Protein kinase D3 sensitizes RAF inhibitor RAF265 in melanoma cells by preventing reactivation of MAPK signaling. Cancer Res 2011 Apr 28.
4. Zitzmann K, de Toni E, et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer 2011 Mar 21; 18(2):277-85.

Sunday, March 25, 2012



The inhibitors to HDACs, target various HDAC enzymes and some of them are highly efficient against solid tumors. Some inhibitors need to be administered for a prolonged period of time. JNJ-26481585 is one such inhibitor which belongs to the group of 2nd generation of inhibitors. Under in vivo conditions it shows pharmacodynamic response for a prolonged period of time.


The inhibitors to HDACs generally show a potent action against HDACs belonging to class I, IIa and IIb. The HDAC enzymes belonging to class II are not generally involved in the survival of the solid cancers. Hence inhibition of this set of enzymes does not generally effect the growth and proliferation of tumor. The inhibitors to HDAC6 (belonging to the class IIb HDAC) decrease the movement of the cells. It also acts on ongogenic proteins like Hsp90 and depletes their levels. Inhibitors like paclitaxel and bortezomib show same effect. However the effects of these inhibitors were limited. Then the search began for some substances which can show potent anti-tumor activity and can efficiently inhibit the HDACs belonging to class I. After analyzing 140 lead compounds which were derived from pyrimidyl-hydroxamate, JNJ-26481585 was identified. In case of colon cancer cells it stimulated the hyperacetylation of histone H3. This further inhibited the tumor growth completely. It is presently undergoing clinical trials to prove its efficacy against various tumors [1].


The pan-HDAC inhibitor JNJ-26481585 was tested in case of multiple myeloma cell lines (both primary and established in nature). It promoted the acetylation of the histones and increased the levels of those proteins which are members of Bcl2 family and promote apoptosis. It arrests the induction of Hsp72 and growth pathway. At a very low concentration it depletes the levels of Mcl-1 protein and stimulates the death of the myeloma cells [2].


Multiple myeloma is a malignancy within B-cells and is usually associated with severe bone disease and other complications. It leads to bone lesions which are lytic in nature and the skeletal events are disturbed. Biphosphonates are generally used for supportive care but they do not show any specific action towards bone lesions. Bortezomib was administered along with JNJ-26481585 on 5T2MM model. The combined effect of these inhibitors was a reduction in the number of osteoclasts along with an increase in the number of osteoblasts.  The number and the bone volume of the trabecular bone were found to be increased. Angiogenesis is controlled and the tumor burden is reduced. The bone remodeling properties of Bortezomib were further enhanced by JNJ-26481585 hence making this combination highly efficient against multiple myeloma [3]. The microenvironment of the bone marrow generally offers drug resistance and hence makes multiple myeloma incurable. JNJ-26481585 upregulates p21 and activates the caspase cascade. This affects the cell cycle by arresting it and stimulates the process of apoptosis within myeloma cells. It was selective in its action and showed no adverse effects within endothelial cells. It was potent at low concentrations.


JNJ-26481585 is effective in controlling the growth of myeloma and it enhances the efficiency of other inhibitors.


1. Arts J, King P, et al. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res 2009 Nov 15; 15(22):6841-51.
2. Stühmer T, Arts J, et al. Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585. British Journal of Haematology 2010 May; 149(4): 529–536.
3. Deleu S, Lemaire M, et al. Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma. Cancer Res 2009 July 1; 69(5307).
4. Deleu S, Lemaire M, et al. The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine modelsThe effect of JNJ-26481585 in murine myeloma models. Leukemia 2009 Oct; 23(10):1894-903.

Friday, March 23, 2012



Certain forward and backward modifications are facilitated by a set of enzymes which are known as HATs and HDACs. They maintain a balanced acetylation of the histone proteins. A decrease in the quantity of HATs leads to excess deacetylation of histone proteins. This further stimulates the neuronal degeneration. HDAC inhibitors like Valporate, Vorinostat and ITF2357 help in treating neuronal disorders.


A mouse suffering from head injury was chosen and was examined after the treatment with ITF2357. It is a hydroxamic acid derivative which did not show any organ toxicity under physiological conditions. After administration at a concentration of 1.5 mg/kg/day, the pain in the joints was reduced significantly. It inhibits the damage to the tissues after 24 hours of administration. It brings down the degeneration of the neuronal tissues and reduces the lesion volume. The acetylation of the histone H3 proteins is stimulated. An injury decreases the levels of the HSP70 kDa and pAkt. This decrease in the levels is halted by ITF2357. This is also accompanied with the increase in p53 levels as a result of which the cells are cleared out by the process of apoptosis, at an increased rate [1].


Mutation within the Jak2 kinase (replacement of valine residue with phenyl alanine) is associated with polycythemia vera. ITF2357 shows specific action against those cells showing this mutation. Low concentrations of ITF2357 ranging from 0.001–0.01μM were enough to control the growth of these mutated cells. The concentration of ITF2357 required to inhibit the growth of the normal or tumor cells was found to be at least 100 -250 times greater.   In fact ITF2357 stimulates the outgrowth of the unmutated colonies. The total and p JAK2V617F molecules disappear totally after the administration of ITF2357. The phosphorylated levels of STAT5 and STAT3 were also found to be significantly reduced. The mRNA of JAK2V617F was inhibited from getting modified within granulocytes. On the whole this inhibitor checks the proliferation of cells showing JAK2V617F mutation hence downmodulating the mutated protein [2].


The proapoptotic signals are suppressed in many cases of cancers as a result of which the cells become resistant to cell death. Agents like SAHA or trichostatin A which inhibit HDACs stimulate the expression of these genes. This later promotes apoptosis or terminal differentiation. These inhibitors bind to the zinc atom in the catalytic pocket and hence inhibit its catalytic properties. Within the LPS stimulated PMBCs, ITF2357 reduced the levels of TNFα, IL-1β, IFNγ and IL-1α at different concentrations. It decreases the mRNA levels of TNFα [3].


ITF2357 targets HDACs belonging to class I and II. During diabetes various proinflammatory cytokines are produced which destroy the β-islet cell. ITF2357 acts both as HDAC inhibitor and anti-inflammatory agent. The effect of ITF2357 was further confirmed after noticing the increase in the insulin synthesis. It decreases the apoptosis of β-islet cells drastically [4].


In a nut shell ITF2357 not only checks the growth of tumors but is also helpful in controlling the rate of diabetes and neuronal degeneration.


1. Shein NA, Grigoriadis N, et al. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. The FASEB Journal Dec 2009; 23(12): 4266-4275.
2. V Guerini, V Barbui, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617FThe HDAC inhibitor ITF2357 downmodulates JAK2V617F. Leukemia 2008 April; 22, 740-747.
3. Flavio Leoni, Gianluca Fossati, et al. The Histone Deacetylase Inhibitor ITF2357 Reduces Production of Pro-Inflammatory Cytokines In Vitro and Systemic Inflammation In Vivo. Mol Med 2005 Jan-Dec; 11(1-12): 1–15.
4. Lewis EC, Blaabjerg L, et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol Med 2011 May-Jun; 17(5-6):369-77.