Wednesday, April 25, 2012
VORINOSTAT (SAHA) – A NOVEL INHIBITOR WITH MULTIPLE EFFECTS
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.
VORINOSTAT AND VALAPORATE DEVELOP RESISTANCE IN COLON CANCER CELLS WITHIN HUMAN BEINGS
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 .
VORINOSTAT REGULATES THE TELOMERASE ACTIVITY
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 .
TRANSLATION OF CYCLIN D1 IS SUPPRESSED BY SAHA
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 .
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 .
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.