PARP INHIBITOR: A THERAPEUTIC AGENT FOR ISCHEMIA, STROK AND CANCER

by Selleckchem | Jul 15 2012

USES OF PARP INHIBITOR AND DOWNREGULATION OF PARP CASCADE
Human genome consists of different genes one of which is PARP gene which translates to produce PARP or Poly ADP-ribose polymerases. Important functions of cells like programmed cell death and mechanism of DNA repair is being controlled by these proteins. Breaks in single strand of DNA are specifically repaired by these proteins. Since BRCA1 and BRCA2 are involved in breast and ovarian cancer onset their associations with PARP inhibition have been reported in a number of researches. Because of these details inhibition of PARP has become a vital tool for therapy of various cancers [1]. Against these BRCA genes inhibitors of PARP have shown effective results. PARP inhibitors specifically targets only the cancer cells not normal cells which is their edge point. Conventional therapies have become less famous because mode of action of PARP inhibitor has shown that it is very good against different cancers.

PHARMACOLOGICAL CHARACTERISTICS OF PARP INHIBITORS
15d-PGJ2 and TGZ are the agonists and antagonists for determination of PARP are not ordinary matter in research and development fields [2].Efficiency of PARP inhibitor has been evaluated in various preclinical trials and anyone can buy PARP inhibitor from PARP inhibitor supplier for any purpose. For the assessment of PARP inhibitor before and after administration variety of kit are available in market. siRNA screening is one of the methods that is used to assess PARP inhibitor and other method is direct quantification [4]. When in in vivo studies 3-aminobenzamide, NU1025 and AG14361 were used against breast cancer they revealed a strong link between PARP inhibitor and breast cancer and also their effect was evaluated in mouse deficient of BRCA1 mammary cancer cells [5]. Among the famous and vital therapeutic agents belonging to PARP inhibitor group BSI-201, PJ34ABT888, 5-AIO Olaparin or AZD2281 are worth mentioning.

CLINICAL TRIALS OF PARP INHIBITORS
A number of different compounds are being analyzed that act like PARP inhibitor but only 8 are under clinical studies [6]. A PARP inhibitor in clinical trial is AZD2281 which not only found to inhibit the proliferation of cancer cells but also acted against BRCA in mice which were genetically engineered to have breast cancer [7] and promising results were obtained in phase II clinical trials against ovarian cancer and BRCAness [8]. PJ34 is anti-strok PARP inhibitor which showed fruitful results in in vitro as well as in in vivo models [9]. Effective results were shown when BSI-201 was co-administered with Gemcitabine and Carboplatin against TNBC patients [10]. Outstanding results were reported when 5-AIQ was administered in ischemic patients where it acted as PARP inhibitor [11]. AG-014699 which is also a PARP inhibitor was co-administered with Temozolomide against carcinomas in phase I and proved promising results.

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.