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PARP INHIBITOR: STROKE ISCHEMIA AND CANCER

DEREGULATION OF PARP CASCADE:
In humans, Poly (ADP-ribose) polymerase or PARP enzymes are encoded by PARP gene and regulate some crucial processes in the cells for example programmed cell death or the DNA repair system. They play their role in DNA repair process by repairing the ssDNA or single stranded DNA breaks on DNA. The interaction of BRCA1 and BRCA2 with them is very well documented which links the deregulation of PARP with ovarian and breast cancer because many of these types of cancers are associated with the mutations in BRCA1 and BRCA2 genes. For this reason, the inhibition of PARP is found to be an attractive therapeutic approach [1] due to the specificity and effectiveness of PARP specific inhibitors against the cancers caused by BRCA genes. An inhibitor having specificity for PARP exhibits good results due to high sensitivity of cancer cells against PARP inhibiting drugs leaving the healthy cells unaffected. Hence the PARP inhibition mechanism has made them an attractive and better choice as compared to the conventional therapies affecting all the healthy cells as well.


PARP INHIBITORS: PHARMACOLOGICAL PROPERTIES
The vivid uses of PARP agonists and PARP antagonists like TGZ and 15d-PGJ2 etc., in the research laboratories are not very surprising for the scientific area [2]. Due to the remarkable promising results shown by the preclinical models of PARP inhibition, a number of inhibitor molecules are designed and the researchers can easily buy them for their laboratory and research purposes from the respective suppliers. To perform a PARP activity assay while testing, before and after the inhibitor treatment, different kits are commercially available in the market. This PARP activity assay can be carried out by using direct quantification method [4] or by using the siRNA screen [3]. After the great success of drugs named 3-aminobenzamide, AG14361 and NU1025 in the in vivo model of mammary tumors which were deficient in BRCA1 and derived from human breast cancer cell lines and BRCA1 deficient mouse, a remarkable link between breast cancer and PAPR inhibitors was developed and elaborated [5]. Different PARP inhibitors that are in use for the PARP inhibition and cancer treatment are AZD2281 or Olaparib, BSI-201, 5-AIO and PJ34ABT888 etc.


PARP INHIBITORS: CLINICAL STUDIES
According to a recent study, there are eight PARP inhibitors that are being tested in the clinical trials [6]. Success of PARP inhibitors in the clinical testing can be stated by giving example of drug known as AZD2281 in increasing the toxicity free cell survival and inhibiting the growth of tumor in genetically engineered mice model of breast cancer associated with BRCA1 where it has shown remarkable efficiency in clinical trials phase II involving the ovarian cancer patients also revealing a link between ovarian cancer, PARP inhibitor and BRCAness [8]. PJ34 PARP inhibitor was used in different in vivo and in vitro stroke models [9]. Another clinical trial of phase II involving the patients of TNBC or metastatic form of triple-negative breast cancer showed synergistic efficiency of BSI-201 with Carboplatin and Gemcitabine [10]. 5-aminoisoquinolinone or 5-AIQ is another PARP inhibitor that has shown the reduction in tissue injury post ischemia resulting from the liver reperfusion [11]. Another PARP inhibitor, AG-014699 was tested in combination with TMZ or Temozolomide in patients suffering from advanced solid tumor in a clinical trial phase I [12].


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.
 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S2178 AG-14361 AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM in a cell-free assay. It is at least 1000-fold more potent than the benzamides. (25) (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. (838) (18)
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. (13) (3)
S1004 Veliparib (ABT-888) Veliparib (ABT-888, NSC 737664) is a potent inhibitor of PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM in cell-free assays, respectively. It is inactive to SIRT2. Veliparib increases autophagy and apoptosis. Phase 3. (194) (10)
S1098 Rucaparib (AG-014699) phosphate Rucaparib (AG-014699, PF-01367338) is an inhibitor of PARP with Ki of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3. (104) (8)

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