ABSTRACT
Our understanding of the progression and mechanisms underlying the onset of Parkinson's disease (PD) has grown enormously in the past few decades. There is growing evidence suggesting that poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation is involved in various neurodegenerative disorders, including PD, and that poly (ADP-ribose) (PAR)-dependent cell death is responsible for neuronal loss. In this review, we discuss the contribution of PARP-1 and PAR in the pathological process of PD. We describe the potential pathways regulated by the enzyme, review clinically relevant PARP-1 inhibitors as potential disease-modifying therapeutics for PD, and outline important factors that need to be considered for repurposing PARP-1 inhibitors for use in PD.
Subject(s)
Neurodegenerative Diseases , Parkinson Disease , Cell Death , Humans , Neurodegenerative Diseases/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Poly Adenosine Diphosphate Ribose/metabolism , Poly Adenosine Diphosphate Ribose/pharmacology , Poly Adenosine Diphosphate Ribose/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic useABSTRACT
The use of the PARP inhibitors (PARPi) in the treatment of breast cancer (BC) with germine mutations has evolved over the years, and further research has been done in order to broaden the horizon of this treatment strategy. Therefore the aim of this paper is to review the efficiency of PARPi in the treatment of BRCA 1/2-mutated locally advanced and metastatic Her-2/net negative BC mentioning their side effects, mechanism of resistance and future directions. Inhibition of PARP transforms single-strand breaks into double-strand breaks (DBS), the accumulation of the latter causing cell death (cell apoptosis). The Olympia AD phase III trial demonstrated a statistically significant progression-free survival rate (PFS) when using the PARPi olaparib in metastatic BC with germline BRCA1/2 mutations without any benefit of the overall survival rate. PARPi therapy is associated with acceptable responsive rates and progression-free survival rates in locally advanced and metastatic BRCA1/2 associated BC through mechanisms that enhance and increase the sensitivity to chemotherapeutic or target agents as they induce a synthetic lethality and cell apoptosis. The side effects are not significant, the most adverse effects being related to the hematological and gastrointestinal systems. Olaparib is currently approved in the first-line treatment of BRCA1/2 mutated Her-2/neu negative metastatic BC at an oral dose of 300 mg twice daily, while Talazoparib represents a category one recommendation in locally advanced and metastatic Her-2/neu negative BC in women with central nervous system metastases.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Germ-Line Mutation/genetics , Poly Adenosine Diphosphate Ribose/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Breast Neoplasms/pathology , Female , Humans , Neoplasm Metastasis , Poly Adenosine Diphosphate Ribose/therapeutic useABSTRACT
Poly(ADP-ribose), identified in 1966 independently by three groups Strassbourg, Kyoto and Tokyo, is synthesized by poly(ADP-ribose) polymerases (PARP) from NAD(+) as a substrate in the presence of Mg(2+). The structure was unique in that it has ribose-ribose linkage. In the early-1970s, however, its function in vivo/in vitro was still controversial and the antibody against it was desired to help clear its significance. Thereupon, the author tried to produce antibody against poly(ADP-ribose) in rabbits and succeeded in it for the first time in the world. Eventually, this success has led to the following two groundbreaking papers in Nature: "Naturally-occurring antibody against poly(ADP-ribose) in patients with autoimmune disease SLE", and "Induction of anti-poly(ADP-ribose) antibody by immunization with synthetic double-stranded RNA, poly(A)·poly(U)".On the way to the publication of the first paper, a reviewer gave me a friendly comment that there is "heteroclitic" fashion as a mechanism of the production of natural antibody. This comment was really a God-send for me, and became a train of power for publication of another paper, as described above. Accordingly, I thought this, I would say, episode is worth describing herein. Because of its importance in biomedical phenomena, a certain number of articles related to "heteroclitic" have become to be introduced in this review, although they were not always directly related to immuno-biological works on poly(ADP-ribose). Also, I tried to speculate on the future prospects of poly(ADP-ribose), product of PARP, as an immuno-regulatory molecule, including either induced or naturally-occurring antibodies, in view of "heteroclitic".
Subject(s)
Poly Adenosine Diphosphate Ribose/immunology , Poly Adenosine Diphosphate Ribose/therapeutic use , Animals , Antibodies/immunology , Histones/immunology , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Nerve Degeneration/drug therapy , Nerve Degeneration/immunology , Poly Adenosine Diphosphate Ribose/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic useABSTRACT
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