PARP INHIBITOR: TREATMENT OF STROK, ISCHEMIA AND CANCER

by Selleckchem | Sep 09 2012

DEREGULATION OF PARP CASCADE AND ITS APPLICATIONS:
Poly ADP-ribose polymerases or PARP are the translated product of PARP genes located in human genome. These proteins play some of the vital roles in the cell such as apoptosis and DNA repair mechanism. The repair mechanism of DNA is specific for the single stranded DNA (ss DNA) breaks. A reasonable work has been reported about the interaction of BRCA1 and BRCA2 and this knowledge leads to the understanding of PARP deregulation causes or links with ovarian and breast cancer as different research reports concluded the mutations of these two genes are present in these cancers. Due to these reasons the PARP inhibition mechanism has become an efficient therapeutic tool for cancer treatment [1]. The specific PARP inhibitors may have efficient results against tumors and cancers with BRCAness. The beauty of these PARP inhibitors is that the normal cells are not affected where tumors cells are only targeted. Mechanism of PARP inhibitor tells about the efficacy of these inhibitors in treatment of cancers and because of their efficient actions the old therapies are becoming less popular as they affect the normal cells as well.

PARP INHIBITORS PHARMACOLOGICAL PROPERTIES
Antagonists and agonists of PARP determination for example TGZ and 15d-PGJ2 etc is not an uncommon issue in the field of research and development [2]. Preclinical studies on various models have determined the efficacy of PARP inhibitors many of the compounds are designed for this purpose and one can purchase PARP inhibitors for research and lab use from any of the PARP inhibitor supplier. Commercially available kits can be used for the determination of PARP inhibitors effects prior and after treatment with these compounds. There are two methods which are also used for the PARP protein inhibitor assay including siRNA screening [3] or direct quantification method [4]. A solid link between breast cancer and PARP inhibitors was analyzed when AG14361, NU1025 and 3-aminobenzamide was used against cells of breast cancer in in vivo conditions, in addition to this the action of these inhibitors was also noted in mouse model lacking BRCA1 mammary tumor cells [5]. AZD2281 or 5-AIO Olaparin, BSI-201 and PJ34 ABT888 are among some of the therapeutically important agents which work as PARP inhibitors.

PARP INHIBITORS UNDER CLINICAL TRIALS
There are many compounds reported which work as PARP inhibitors but in recent clinical trials studies only 8 molecules are undergoing these studies [6]. A famous example is of AZD2281 PARP inhibitor in clinical trial which proved to inhibit the growth of tumor and cancer cells and in addition to this it also enhanced the toxicity free survival rate in BRCA1 related genetically engineered model of mice (GEMM) having breast cancer [7], during clinical trials phase II these this inhibitor has proven efficient in treating patients with linking ovarian cancer, ovarian cancer and also BRCAness [8]. PARP inhibitors for the treatment of stroke include PJ34 which was analyzed on various in vivo and in vitro models and effective results were obtained [9]. For the treatment of TNBC or triple negative breast cancer BSI-201 was administered along with Carboplatin and Gemcitabine and this inhibitor also proved as effective [10]. 5-AIQ or 5-aminoisoquinolinone was also used as a PARP protein inhibitor against a condition which is caused by the liver reperfusion called ischemia and good results were noted [11]. AG-014699 is another PARP inhibitor which is undergoing phase I of clinical trials against solid tumor with another drug called Temozolomide and reported an efficient 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.
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.
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.
S1004	Veliparib (ABT-888)	Veliparib (ABT-888, NSC 737664) is a potent inhibitor of PARP1 and PARP2 with K_i 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.
S1098	Rucaparib phosphate	Rucaparib phosphate is an inhibitor of PARP with K_i of 1.4 nM for PARP1 in a cell-free assay, also showing binding affinity to eight other PARP domains. Phase 3.