HDAC Flashcards
Short Chain Fatty Acids
Valporic Acid
* a histone deacetylase inhibitor
(HDACI), in vitro induces differentiation of promyelocyte leukemia cell and proliferation arrest and apoptosis of various leukemia cell lines.
Hydroxamic Acid
Trichostatin A (TSA)
* Hydroxamic acid
* Reversible inhibitor of Histone deacetylase
* Induce cell cycle arrest at G1, apoptosis, and cellular differentiation
* Has some uses as anti- cancer drug
tetrapeptides
Cyclic tetrapeptides : Depsipeptide
* Modulate the expression
of genes
* Two drugs undergoing clinical trial
– MS-275
* A substance that is being studied in the treatment of cancers of the blood
* Mice experiment and result
– CI-994
* Mechanism of antitumor activity unclear
* Causes accumulation of acetylated histones although is not able to inhibit HDAC activity in a direct fashion
HDAC and cancer
- A common finding in cancer cells is high level expression of HDAC isoenzymes and a corresponding hypoacetylation of histones.
- An attractive model for the antitumor action of HDAC inhibitors is that the increase in histone acetylation leads to the activation of transcription of a few genes of which the expression causes the inhibition of tumor growth.
- In vitro and in vivo, HDAC inhibitors cause cell cycle arrest and differentiation of many tumor types.
- HDAC mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, nuclear factor B (NF-B), hypoxia-inducible factor 1 (HIF-1), as
well as Estrogen Receptor and Androgen Receptor complexes. - BCR-ABL, epidermal growth factor receptor, human epidermal growth factor receptor 2/neu, FLT3, Akt, and
c-Raf
PPAR
- The peroxisome proliferator-activated receptors (PPARs) comprise an important subfamily of the
nuclear hormone receptor (NHR) superfamily. - The name PPAR derives from the initial cloning of one isoform as a target of various xenobiotic
compounds that were observed to induce proliferation of peroxisomes in the liver. This protein was called the peroxisome proliferator-activated
receptor, now known as PPARα. The group of PPARs was expanded to include PPAR and PPAR (also
referred to as PPAR, NUC1, and FAAR).
PPAR and DNA
- N-terminal region that contains a potential trans-activation function known as AF-1, followed by a
DNA binding domain that includes two zinc fingers.
At the carboxyl terminus is a dimerization and ligand binding domain that molecular modeling reveals to be a large hydrophobic pocket and which contains a
key, ligand dependent trans-activation function called AF-2.
* PPARs bind to cognate DNA elements called PPAR response elements (PPREs) in the 5-flanking region of target genes.
PPAR-protein interaction
PPARs, like other NHRs, form protein-protein interactions with a variety of nuclear proteins known as coactivators and corepressors, which mediate contact between the PPAR-RXR heterodimer, chromatin, and the basal transcriptional machinery and which promote activation and repression of gene expression.
PPARy ligands
- PPARg ligands encompass wide range of structurally diverse compounds, natural and synthetic.
- Natural ones include long chain polyunsaturated fatty acids and derivatives (eicosanoids, prostaglandins, like 15-deoxy-Δ12,14- prostaglandin J2 (15D-PGJ2)).
- The thiazolidinedione drugs are used for the treatment of type II diabetes and specifically target PPARg.
PPARy regulation
(a) Positive and negative regulators of the PPARγ gene transcription.
(b) The regulation of PPARγ levels by Rb and E2F.
(c) The mechanism of ligand-dependent PPARγ activation.
(d) The regulation of PPARγ activity by MEK and Erk kinases:
MEK1 activates Erk-1/2, which phosphorylates PPARγ and targets it to proteasomes; in addition, MEK1 binds PPARγ in the nucleus and exports it to the cytoplasm. MEK5 can serve as coactivator for the PPARγ.
COX
Prostaglandins are a family of chemicals that are produced by the cells of the body and have several important functions.
They promote inflammation, pain, and fever; support the blood clotting function of platelets; and protect the lining of the stomach from the damaging effects of acid.
Prostaglandins are produced within the body’s cells by the enzyme cyclooxygenase(COX).
NSAIDs
- There are two COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever.
- COX-1 is a constitutively expressed enzyme with a “house-keeping” role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid.
- Most NSAIDs act as non-selective inhibitors of the both COX-1 and COX-2.
COX and cancer
- COX-2 is known to produce prostaglandins that regulate tumor-associated angiogenesis, modulate the immune system, regulate cell migration/invasion, and inhibit apoptosis, all of which promote cancer progression.
- Byproducts of the COX-2 pathway, such as malondialdehyde, directly form DNA adducts resulting in mutations that could initiate carcinogenesis.
- One of the major prostaglandin products of the COX- 2 pathway in the gastrointestinal tumor microenvironment is PGE2.
- PGs produced by COX-1 from epithelial and stromal cells in the subepithelial tissue of the colon are thought to maintain mucosal homeostasis.
Challenge of using NSAIDs for cancer therapy
However, COX-2–derived PGE2 has been shown to be proinflammatory, mediating the progression of diseases such as arthritis and cancer
A steady-state level of PGE2 is maintained in the tumor microenvironment by (a) a biosynthetic pathway, including PG synthases mPGES and cPGES, which converts PGH2 into PGE2, and (b) a catabolic pathway involving 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades PGE2 to an inactive 15-keto PGE2 metabolite. Loss of 15-PGDH expression correlates with tumor formation.
Restoration of 15-PGDH expression strongly inhibited growth of colon cancer xenografts, suggesting that 15-PGDH may have a tumor-suppressor function.
