**2.1 Free radical cause nitric oxide**

The nitric oxide (NO) has dual role in health and disease and depends on its concentration. Nitric oxide is the active marker of the development of cancer by induction of angiogenesis, blood vessel formation during physiological and pathological processes [25]. NO may modulate tumor DNA repair mechanisms by upregulating p53, poly (ADP-ribose) polymerase, and DNA-dependent protein kinase (DNA-PK). The role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease [26]. Alterations in the NO metabolism and to increase protein nitration may contribute to the mutagenic processes and promote lung carcinogenesis [27]. NO promotes intravasation and angiogenesis to enhance cancer cell growth and increase the properties of cancer cells [28].

#### **Figure 4.** *The role of nitric oxide in various diseases of humans [57].*

In lung cancer, a high level of NO is linked to chronic stages of cancer cells and protective role in the survival and proliferation of tumor cells by inhibiting apoptosis, increasing cell migration, and invasion [29]. NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents have NO-modulating properties with safe cytotoxic profile [30]. The nitric oxide synthase 2-mediated production of NO/reactive nitrogen oxide species (RNS) is heavily involved in cancer progression and metastasis in different types of tumor (**Figure 4**) [31].
