**3.2 Oxidative stress in cancer**

Cancer is a multistage process defined by at least three stages: initiation, promotion, and progression [62]. ROS from both endogenous and exogenous sources result in increased oxidative stress in the cell. Oxidative stress modulates gene expression of downstream targets involved in DNA repair, cell proliferation and in part through activation or inhibition of transcription factors and second messengers. The role of single nuclear polymorphism for oxidative DNA repair and enzymatic antioxidants is important in determining the potential human cancer risk [34].

ROS regulates tumor development including following steps: transformation [63], survival [64], proliferation [65], invasion [66], metastasis [67], and angiogenesis [68]. One study showed the oxidative stress may be positive correlation with lung cancer staging [69]. In breast carcinomas, 8-OHdG (a most widely used fingerprint of radical attack towards DNA) might be increased 8- to 17-fold in breast primary tumors compared with non-malignant breast tissue [70].

H2O2 plays an important role in carcinogenesis because it is capable of diffusing throughout the mitochondria and across cell membranes and producing many types of cellular injury [71]. ROS may down-regulate the expression of the DNA mismatch repair genes (mutS homolog 2 and 6) and inhibit its enzymatic activity. ROS also induce the expression of DNA methyltransferases, leading to a total hypermethylation of the genome [72]. DNA methylation silence several tumor suppressor genes promoter, such as adenomatous polyposis coli (APC), cyclin-dependent kinase inhibitor-2 (CDKN-2), breast cancer susceptibility gene 1 (BRCA1), retinoblastoma protein (Rb), and the DNA mismatch repair gene, human mutL homolog 1 (hMLH1) [73, 74].

However, it is interesting that oxidative stress induces cancer, but also exists opposite condition. When ROS produced in large excess, they endanger the viability of the cancer cells, through the sustained activation of the cell cycle inhibitors [75]. To protect themselves from ROS-mediated toxicity, many types of cancers enhance the intrinsic antioxidant defenses, which make them dependent on the efficacy of a given ROS-detoxifying system. This poses an attractive target for anticancer therapy by using prooxidants or inhibiting of a chosen antioxidant system [76]. Whether ROS promote tumor cell survival or act as anti-tumorigenic agents depends on the cell and tissues, the location of ROS production, and the concentration of individual ROS.
