title: Molecular inhibitors of DNA repair: searching for the ultimate tumor killing weapon.
abstract: DNA repair (DR) inhibitors are small molecules that interact with DR proteins in order to disrupt their function and induce a 'strike' to the high fidelity of the mammalian DNA repair systems. Many anticancer therapies aim to harm the DNA of the usually highly proliferative cancer cell, causing it to undergo apoptosis. In response to this, cancer cells attempt to fix the induced lesion and reconstitute its genomic integrity, in turn reducing the efficacy of treatment. To overcome this, DR inhibitors suppress DNA repair proteins' function, increasing the potency and tumor killing effect of chemotherapy or radiotherapy. In this review, we discuss clinically applied novel inhibitors under translational investigation and we apply bioinformatic tools in order to identify repair proteins implicated in more than two phenomenically distinct DNA repair pathways (e.g., base excision repair and nonhomologous end joining), that is, the concept of 'synthetic lethality'. Our study can aid towards the optimization of this therapeutic strategy and, therefore, maximizing treatment effectiveness like in the case of radiation therapy.
authors: Physics Department, School of Applied Mathematical & Physical Sciences, National Technical University of Athens (NTUA), Iroon Polytechniou 9, Zografou 15780, Athens, Greece.
authors: Zacharenia
authors: Z
authors: Nikitaki
authors: Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens (BRFAA), 4 Soranou Efesiou, Athens 11527, Greece.
authors: Ioannis
authors: I
authors: Michalopoulos
authors: Physics Department, School of Applied Mathematical & Physical Sciences, National Technical University of Athens (NTUA), Iroon Polytechniou 9, Zografou 15780, Athens, Greece.
authors: Alexandros G
authors: AG
authors: Georgakilas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004247:DNA
keywords: DNA damage; DNA repair; DNA repair inhibitors; cancer therapy; clustered DNA lesions; multipathway lethality; synthetic lethality