PARP INHIBITOR: CANCER, ISCHEMIA AND STROKE

by Selleckchem | May 15 2012

IMPLICATION OF DEREGULATION OF PARP CASCADE:
PARP or Poly ADP-ribose polymerase enzymatic proteins are encoded by PARP genes in human, and are responsible of regulating the critical cellular processes for example, programmed cell death and DNA repair channel. They play their role in DNA repair pathway by repairing the single-stranded DNA breaks (ssDNA). The interaction of BRCA1 and BRCA2 with them is very well documented that describes a link between PARP deregulation and ovarian and breast cancer, as many among these cancers are associated with the mutations inside these two genes. This is why the PARP inhibition process has proved to be an attractive therapeutic tool [1] and PARP specific inhibitor molecule may prove highly effective against tumors with BRCAness. Generally PARP selective inhibitor exhibits good results due to the tumor cells beings highly sensitive for PARP inhibitor drug leaving the remaining healthy cells. Hence PARP inhibitor mechanism has made them a better choice as compare to the conventional therapies that must affect all the cells irrespective of their status.

PARP INHIBITORS: PHARMACOLOGICAL PROPERTIES
It is not amazing to determine the brilliant uses a PARP agonist and a PARP antagonist like TGZ and 15d-PGJ2 etc., has in research field [2]. Riding high on reports of shining results of PARP inhibition in the preclinical models, various molecules are being generated and one can very easily purchase PARP inhibitor to use in laboratory and for research purposes from PAPR inhibitor suppliers. Various commercial kits are available to perform PARP activity assay after and before the treatment with inhibitor. PARP protein inhibitor assays can also be carried out by using siRNA screen [3] or by doing direct quantification [4]. Successful association between breast cancer and PARP inhibitors was developed after great success of 3-aminobenzamide, NU1025 and AG14361 in the in vivo human breast cancer cells and BRCA1 deficient mouse derived models of BRCA1-deficient mammary tumors [5]. Among different PARP inhibiting drugs used in research field includes AZD2281 or Olaparib, 5-AIO, BSI-201, PJ34ABT888 etc.

PARP INHIBITORS: CLINICAL TRIALS
According to a current study, the number of recently tested PARP inhibitors in clinical trials is 8 [6]. The remarkable achievements of PARP inhibitor in clinical trials is easily described by mentioning AZD2281 for its capability of inhibiting the cancer growth and enhancing the toxicity free survival rate in a BRCA1 related genetically engineered model of mice (GEMM) having breast cancer [7] when it exhibited good results in clinical trials phase II involving the patients of ovarian cancer linking ovarian cancer, PARP inhibitor and BRCAness too [8]. PARP inhibitor PJ34 was used successfully in various in vivo and in vitro models of stroke [9]. A phase II clinical trial involving patients of metastatic form of TNBC or triple-negative breast cancer exhibited some synergistic efficacious results about BSI-201 with Carboplatin and Gemcitabine [10]. Another PARP protein inhibitor is 5-AIQ or 5-aminoisoquinolinone was observed to lessen the post ischemia tissue injury as result of liver reperfusion [11]. AG-014699 is another PARP inhibitor that was combined with Temozolomide and used against patients of advanced solid tumor under 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.

Cat.No.	Product Name	Information
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.
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.
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.