Other determinants of sensitivity

Naoyuki Okita, Atsushi Shibata

Research output: Contribution to journalArticlepeer-review


Cancer treatments such as radiotherapy and chemotherapy induce DNA damage, which can be a factor determining therapeutic efficacy. A DNA double strand break (DSB) is considered to be the most critical type of DNA lesion, since DSBs cause cell death when they are unrepaired and generate mutations if they are misrepaired. Ionising radiation (IR) produces a broad spectrum of DNA damage, including DSBs, single strand breaks (SSBs) and base damages. Specific poly(ADP-ribose) polymerase (PARP) inhibitors, currently being tested in clinical trials, compromise SSB repair after IR, resulting in the accumulation of replication-associated DSBs. Since replication-associated DSBs are effectively repaired by homologous recombination, PARP inhibition sensitizes cells that are defective in homologous recombination. In addition, PARP inhibition effectively blocks backup DSB repair in cells defective in non-homologous end joining (NHEJ) following IR. Importantly, the sensitization in NHEJ-defective cells occurs independently of DNA replication. In this chapter, we discuss the multiple effects of PARP inhibition in DSB repair-defective cells in the context of the potential availability of PARP inhibitor in clinical use. We further discuss how a PARP inhibitor influences the type of cell death, which may affect prognosis following cancer treatment. In cancer therapy using PARP inhibitors, a comprehensive understanding of PARP signaling from DNA damage to cell death may be required to augment DNA damage-induced cell death and to direct restrained cell death in order to reduce inflammation responses in surrounding tissues.

Original languageEnglish
Pages (from-to)363-379
Number of pages17
JournalCancer Drug Discovery and Development
Publication statusPublished - 2015
Externally publishedYes


  • Necrosis vs apoptosis
  • NHEJ
  • Radiotherapy
  • Replication-independent sensitization

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Drug Discovery


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