Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a key feature of cancer development, often associated with the acquisition of mutations in oncogenes, tumor suppressor genes, and DNA repair genes [1]. Thus, DNA repair pathways and cell cycle checkpoint controls have important consequences for genome stability, and have come under much scrutiny [2]. Defects in genome stability increase the sensitivity of cells to DNA damaging agents, and provide an "Achilles heel" for cancer therapeutics [3]. Indeed, there are numerous efforts to manipulate the DNA damage response so as to selectively induce tumor cell death through catastrophic genomic instability [4,5]. Differences in the DNA damage response between normal cells and cancer cells often underlie the utility of DNA damaging agents in cancer treatment. Radiotherapy and chemotherapeutic drugs are known to function by DNA damage-induced tumor cell death, and there are ongoing efforts to improve sensitivity while overcoming resistance to these agents. Poly(ADP-ribose)polymerase (PARP) inhibitors that target defects in double-strand break repair in women with hereditary breast cancer [6] illustrate the concept of selective "synthetic lethality". Other examples include inhibitors of apurinic/apyrimidinic endonuclease-1 (APE1), DNA repair protein RecA homolog (RAD51), ataxia-telangiectasia mutated (ATM), and DNA-dependent protein kinase (DNAPK), some of which have entered clinical trials. As we learn more about the DNA damage response pathways dysregulated in cancer cells, new combinations of agents are being developed with enhanced therapeutic efficacy [7].Epigenetic mechanisms influence DNA damage and repair pathways; the reader is referred to related reviews in the current journal [8-10]. In eukaryotic cells, DNA damage repair occurs in the context of chromatin, and it is now clear that DNA damage response impacts specific aspects of chromatin structure and chromatin remodeling. Post-translational histone modifications, histone variants, and chrom