VORINOSTAT (SAHA)
– A NOVEL INHIBITOR WITH MULTIPLE EFFECTS
INTRODUCTION
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 [1].
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 [2].
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 [3].
CONCLUSION
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].
REFERENCES
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.
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