Abstract
Small molecule inhibitors targeting DNA repair pathways in cancer cells is a novel and promising approach in cancer therapy, which can improve current therapeutic regimen. Although various attempts have been made for designing inhibitors against DNA damage response and repair proteins, reports on Nonhomologous End Joining (NHEJ) inhibitors are limited. Of the several chemical moieties identified, SCR7 and its oxidized form are novel and potent DNA Ligase IV inhibitors involved in the abrogation of DNA end joining thereby leading to cell death. In the present study, we have synthesized sodium salt of SCR7 to generate a water-soluble version of the molecule, referred to as water-soluble SCR7 (WS-SCR7). WS-SCR7 inhibits NHEJ in Ligase IV dependent manner, with a subtle effect on Ligase III at higher concentration. No effect on Ligase I mediated joining was observed. WS-SCR7 shows cytotoxicity in cancer cell lines, leading to induction of apoptosis in a dose-dependent manner.
Highlights
DNA double-strand breaks (DSBs) are the most deleterious DNA damage
It is well established that induction of DSBs in cancer cells during radiotherapy or chemotherapy can lead to apoptosis and cell death
Repair of double-strand breaks occurs through two predominant pathways: Homologous Recombination (HR) and Nonhomologous DNA End joining (NHEJ) [5,6,7,8,9]
Summary
DNA double-strand breaks (DSBs) are the most deleterious DNA damage. When left unrepaired, DSBs can result in the accumulation of DNA breaks in the nucleus, chromosomal rearrangements and cell death [1, 2]. Inhibition of DNA repair resulting in accumulation of DSBs is considered as an interesting and novel strategy to treat cancer [3, 4]. Repair of double-strand breaks occurs through two predominant pathways: Homologous Recombination (HR) and Nonhomologous DNA End joining (NHEJ) [5,6,7,8,9]. We have shown that parental SCR7 can get cyclized into a stable form with the same molecular formula and mass, which upon further oxidation can result in SCR7-pyrazine, which possesses a different molecular formula and molecular weight [15] Both forms of SCR7 inhibited NHEJ in vitro and ex vivo, SCR7-pyrazine was less specific inside the cells [15]. WSSCR7 works in Ligase IV dependent manner, leading to accumulation of DSBs and improved cell death
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