<P> ROS - related oxidation of DNA is one of the main causes of mutations, which can produce several types of DNA damage, including non-bulky (8 - oxoguanine and formamidopyrimidine) and bulky (cyclopurine and etheno adducts) base modifications, abasic sites, non-conventional single - strand breaks, protein - DNA adducts, and intra / interstrand DNA crosslinks . It has been estimated that endogenous ROS produced via normal cell metabolism modify approximately 20,000 bases of DNA per day in a single cell . 8 - oxoguanine is the most abundant among various oxidized nitrogeneous bases observed . During DNA replication, DNA polymerase mispairs 8 - oxoguanine with adenine, leading to a G → T transversion mutation . The resulting genomic instability directly contributes to carcinogenesis . Cellular transformation leads to cancer and interaction of atypical PKC - ζ isoform with p47phox controls ROS production and transformation from apoptotic cancer stem cells through blebbishield emergency program, . </P> <P> Uncontrolled proliferation is a hallmark of cancer cells . Both exogenous and endogenous ROS have been shown to enhance proliferation of cancer cells . The role of ROS in promoting tumor proliferation is further supported by the observation that agents with potential to inhibit ROS generation can also inhibit cancer cell proliferation . Although ROS can promote tumor cell proliferation, a great increase in ROS has been associated with reduced cancer cell proliferation by induction of G2 / M cell cycle arrest; increased phosphorylation of ataxia telangiectasia mutated (ATM), checkpoint kinase 1 (Chk 1), Chk 2; and reduced cell division cycle 25 homolog c (CDC25). </P> <P> A cancer cell can die in three ways: apoptosis, necrosis and autophagy . Excessive ROS can induce apoptosis through both the extrinsic and intrinsic pathways . In the extrinsic pathway of apoptosis, ROS are generated by Fas ligand as an upstream event for Fas activation via phosphorylation, which is necessary for subsequent recruitment of Fas - associated protein with death domain and caspase 8 as well as apoptosis induction . In the intrinsic pathway, ROS function to facilitate cytochrome c release by activating pore - stabilizing proteins (Bcl - 2 and Bcl - xL) as well as inhibiting pore - destabilizing proteins (Bcl - 2 - associated X protein, Bcl - 2 homologous antagonist / killer). The intrinsic pathway is also known as the caspase cascade and is induced through mitochondrial damage which triggers the release of cytochrome c . DNA damage, oxidative stress, and loss of mitochondrial membrane potential lead to the release of the pro-apoptotic proteins mentioned above stimulating apoptosis . Mitochondrial damage is closely linked to apoptosis and since mitochondria are easily targeted there is potential for cancer therapy . </P> <P> The cytotoxic nature of ROS is a driving force behind apoptosis, but in even higher amounts, ROS can result in both apoptosis and necrosis, a form of uncontrolled cell death, in cancer cells . </P>

The formation of free radicals or reactive oxygen species (ros) is related to