Chemotherapeutic Compounds Targeting the DNA Double-Strand Break Repair Pathways: The Good, the Bad, and the Promising

Abstract

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.

The Role of HMGB1 in Radioresistance of Bladder Cancer

“…Alongside MRE11, ATM is also known to play a central role in DNA damage repair and cellcycle checkpoints and has been thoroughly investigated in the field of radiosensitization (35). ATM inhibitors like KU-55933 and CP466722 have shown promising radiosensitization in vitro and in preclinical studies (38,39). Recently, KU-55933 has also been implicated in DAB21P-defective bladder cancer radiosensitivity (40).…”

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

“…Recent work showed that exposure to hyperthermia can restrict the activity of DNA-PKs in addition to reducing protein levels of KU70, KU80, BRCA1 and 53BP1 with the first two in greater extent [94]. Finally, given that various chemotherapeutic agents have the ability to trigger the induction of DSBs, inhibitors of DNA ligases and/or DNA-PKs appear to sensitize tumor cells to chemotherapeutic drugs thus providing alternative therapeutic strategies which potentially can be more effective [95,96]. To this end, it can be speculated that exposure to hyperthermia in combination with various inhibitor drug molecules might have a significant impact on the NHEJ pathway and thus provide in potentiating their therapeutic effectiveness.…”

DNA Repair Mechanisms

“…MRN kompleksi tarafından gerçekleştirilen bu kesim, HR'nin erken aşamasında, MRN kompleksi ile CtIP'nin etkileşimi sonucunda uyarılmaktadır. Mre11 tarafından kesimin başlamasını takiben, tek zincir DNA'nın uzun şekilde gerilmesini sağlamak için Exo1 daha kapsamlı bir kesim uygular.Bir tek zincir DNA bağlayan heteromerik kompleks olan RPA (Replikasyon proteini A) uzamış tek zincir DNA'ya bağlanır ve BRCA1 tarafından lezyon bulunduğu bölgede kalması sağlanır 24 .RPA'nın bağlanmasıyla tek zincir DNA stabilize hale getirilmekte ve nükleazlardan korunması sağlanmaktadır 2 . RPA, BRCA2 tarafından DNA'ya yüklenmiş olan rekombinaz Rad51 aracılığı ile DNA'dan çıkartılır.…”

“…RPA, BRCA2 tarafından DNA'ya yüklenmiş olan rekombinaz Rad51 aracılığı ile DNA'dan çıkartılır. Rad51, tek zincir DNA boyunca bir nükleoprotein filamenti oluşturur ve bu filament kardeş kromatidin zincir invazyonuna izin veren bir fonksiyona sahiptir 24 . Rad51 nükleoprotein filamenti ile kaplanmış tek zincir DNA sağlam homolog DNA bölgesinin zincir invazyonunu gerçekleştirir.…”