PARP INHIBITOR: ISCHEMIA, STROK AND CANCER

by Selleckchem | Jun 24 2012

PARP CASCADE DEREGULATION AND ITS IMPLICATION:
PARP are Poly ADP-ribose polymerases and translated by PARP genes present in human genome. These proteins are important for the regulation of critical processes such as DNA repair mechanism and programmed cell death. The DNA repair mechanism based on these enzymes is specific for ssDNA (single stranded DNA) breaks. A sufficient data is available on the BRCA1 and BRCA2 interaction which leads to the concept of PARP deregulation link with breast and ovarian cancer because many cases of these cancers reported about the mutations present in these two genes. Because of this reason PARP inhibition mechanism has proved as an effective therapeutic tool [1] where inhibitors specific for PARP may have effective results against cancers and tumors with BRCAness. PARP inhibitors are mostly specific as the tumor cells are targeted by these molecules therefore the normal cells remain un-affected. The mechanism of PARP inhibitor is so effective against cancer and due to this reason conventional therapies are becoming less useable due to their effects on healthy cells as well.

PHARMACOLOGICAL PROPERTIES OF PARP INHIBITORS
The determination of applications of PARP antagonist and PARP agonist such as 15d-PGJ2 and TGZ ect., is not amazing in research field [2]. The studies on preclinical models has shown significant results of PARP inhibitors, different molecules for this purpose are being discovered and for research use in the laboratory one can buy PARP inhibitors form any of the PARP inhibitors supplier.
In order to analyze the effects of PARP inhibitors commercial kits are available which are used for activity assay before and after treatment with these inhibitors. Another method for PARP protein inhibitor assay is the use of siRNA screening [3] or by direct quantification method [4]. A successful linkage between PARP inhibitors and breast cancer was developed when NU1025, AG14361 and 3-aminobenzamide was used in human breast cancer cells in in vivo, this action was also analyzed in theBRCA1 lacking mouse models derived from BRCA1 deficient mammary tumor cells [5]. There are various therapeutic agents which work as PARP inhibitor including BSI-201, PJ34ABT888, 5-AIO Olaparin or AZD2281 ect.

CLINICAL TRIALS STUDIES OF PARP INHIBITORS
Although various compounds can act like PARP inhibitor but in recent studies only 8 molecules are studied in clinical trials [6]. An outstanding example of PARP inhibitor in clinical trials is AZD2281 which inhibited the growth of cancer and tumors cells and also increased the toxicity free survival frequency in BRCA1 related GEMM (genetically engineered model of mice) having breast carcinoma [7] and it also obtained efficient results in phase II of clinical trials where patients with ovarian cancer, linking ovarian cancer and BRCAness was treated [8]. With respect to treatment of stroke PJ34 was used in different in vitro and in vivo models and good results were reported [9]. BSI-201 along with some other inhibitors including Gemcitabine and Carboplatin was used for the treatment of triple negative breast cancer or TNBC and efficient results were noted [10]. Moreover ischemia tissue damage due to liver reperfusion was also reported to be reduced upon the application of a PARP protein inhibitor named 5-aminoisoquinolinone or 5-AIQ [11]. One more inhibitor of PARP AG-014699 which was used against advanced solid tumor in clinical trial phase I in combination with Temozolomide with good output.

REFERENCES:
1. Rouleau M, e.a., PARP inhibition: PARP1 and beyond. Nature Reviews Cancer, 2010).
2. Liu JJ, e.a., Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-γ agonists induced apoptosis in human monocyte leukemia cells in vitro. Annals of Hematology, 2007.
3. Turner NC, e.a., A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. The EMBO Journal, 2008.
4. Putt KS, e.a., Direct Quantitation of Poly(ADP-Ribose) Polymerase (PARP) Activity as a Means to Distinguish Necrotic and Apoptotic Death in Cell and Tissue Samples. ChemBioChem, 2005.
5. Soto JA, e.a., The Inhibition and Treatment of Breast Cancer with Poly (ADP-ribose) Polymerase (PARP-1) Inhibitors. Int J Biol Sci., 2006.
6. Drew Y, P.R., PARP inhibitors in cancer therapy: Two modes of attack on the cancer cell widening the clinical applications. Drug Resistance Updates, 2009.
7. Rottenberg S, e.a., High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. PNAS, 2008.
8. Audeh MW, e.a., Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol, 2009.
9. Abdelkarim GE, e.a., Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med., 2001.
10. O'Shaughnessy J, e.a., Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol, 2009.
11. Filipe HM, e.a., The novel PARP inhibitor 5-aminoisoquinolinone reduces the liver injury caused by ischemia and reperfusion in the rat. . International Medical Journal of Experimental and Clinical Research, 2002.
12. Plummer R, e.a., First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors. Clinical Cancer Research, 2005.

Cat.No.	Product Name	Information
S2178	AG-14361	AG14361 is a potent inhibitor of PARP1 with K_i of <5 nM in a cell-free assay. It is at least 1000-fold more potent than the benzamides.
S1087	Iniparib (BSI-201)	Iniparib (BSI-201, NSC-746045, IND-71677) is a PARP1 inhibitor with demonstrated effectiveness in triple-negative breast cancer (TNBC). Phase 3.
S1060	Olaparib (AZD2281)	Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations.