A new approach in cancer treatment: poly (ADP-ribose) polymerase-1 inhibitors

Year 2015, Volume: 5 Issue: 1, 41 - 52, 03.05.2015

Fatih Tok Bedia Koçyiğit Kaymakçıoğlu

Abstract

Internal and external factors can damage DNA, the genetic material. Numerous repair mechanisms, which can repair those damages, exist in the normal cell. One of those is called PARP-1 enzyme. PARP-1 transfers ADP-ribose subunits from nicotinamide adenine nucleotide to protein acceptor. Thus, single strand DNA breaks can be repaired. If PARP-1 inhibition occurs, single strand DNA breaks cannot be repaired and double strand DNA breaks can be formed. Eventually, cells undergo necrosis or apoptosis. The aim of cancer treatment is to inhibit the PARP-1 enzyme. For this purpose, many studies have been published over the last decade and currently PARP-1 enzyme inhibitors which are in the phase studies and which are waiting to be marketed are available. In this review, information are given for the mechanisms by which DNA damage is repaired, the protection mechanism of the genomic integrity of PARP enzyme family and chemical structure of PARP-1 inhibitors which are improved to use in cancer treatment.

Keywords

Poly(ADP-ribose) polymerase, molecular modelling, PARP-1 inhibitors, cancer treatment

Kanser tedavisinde yeni bir yaklaşım: Poli (ADP-riboz) polimeraz-1 inhibitörleri

Abstract

Genetik materyal olan DNA’da iç ve dış etkenler sonucu hasar oluşabilir. Normal bir hücrede bu hasarı onarabilecek çok sayıda tamir mekanizması vardır. Bunlardan biri de PARP-1 enzimidir. PARP-1, nikotinamid adenin dinükleotidden ADP-riboz yapılarını protein akseptörüne transfer eder. Böylece tek zincir DNA kırıkları onarılır. PARP-1’in inhibisyonu durumunda ise bu tek zincir DNA kırıkları onarılamaz ve çift zincir DNA kırıkları oluşur. Sonuçta hücre nekrozise ya da apoptozise gider. Kanser tedavisinde tümörlü hücrelerin PARP-1 inhibisyonuyla öldürülmesi amaçlanmaktadır. Bu amaçla son on yıl içinde çok sayıda çalışma yapılmış olup, günümüzde faz aşamasında bulunan ve piyasaya sürülmeyi bekleyen PARP-1 inhibitörleri mevcuttur. Bu derlemede, DNA’da oluşan hasarın hangi mekanizmalarla onarıldığı, PARP enzim ailesinin genomik bütünlüğü nasıl koruduğu ve kanser tedavisinde kullanılmak üzere geliştirilmiş PARP-1 inhibitörü kimyasal bileşiklerin yapıları hakkında bilgi verilmiştir.

Keywords

Poli(ADP-riboz) polimeraz, moleküler modelleme, PARP-1 inhibitörleri, kanser tedavisi

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