**4. Anticancer properties of anthocyanins**

The uncontrolled growth of cells which can invade and spread to distant sites of the body is a global health problem, called cancer, with high mortality. Prevention and routine monitoring are critical to early and accurate diagnosis. Most therapeutic options do not offer cure but rather a deceleration of cancer progression. They not only aim at life extension and the improvement of patients' life quality but also often they have multiple side effects. In recent years, fruit and vegetables, including soft fruits such as berries, may represent a valid alternative than drugs with undesirable side and adverse effects, because of their chemopreventive or chemotherapeutic properties against certain diseases, such as cancer. Recent studies on the cancer preventative activities of the anthocyanins include results from *in vitro* cell culture and *in vivo* animal model tumor systems, as well as data from human epidemiological studies. Cancer cells differ from normal cells by a number of characteristics, thus being different in morphology and function. Anthocyanins can attack cancer cells due to these differences and cause a number of effects. A significant characteristic of cancer cells is their uncontrolled cell cycle, which leads to continuous division and proliferation. Pure anthocyanins and anthocyanin-rich extracts have demonstrated to inhibit cell proliferation by the ability of anthocyanins to block various stages of the cell cycle [46, 47]. Moreover, they can selectively inhibit the proliferation of cancer cells, but have little influence on the proliferation of normal cells [48, 49]. Anthocyanins have demonstrated to induce the apoptosis of cancer cells through the internal mitochondrial pathway and the external death receptor pathway. Usually, apoptosis, the programed cell death, in tumor cells is not present; therefore, dead cells cannot be eliminated normally. Cancer cells have deregulated several genes to avoid the apoptosis, such as p53, and these cells have high resistance to death compared with normal cells. In the intrinsic pathway, cytochrome *c* release and modulation of caspase-dependent anti- and proapoptotic proteins appear as an increase in mitochondrial membrane potential, because of anthocyanin treatment on cancer cells. In the extrinsic pathway, the expression of FAS and FASL is modulated by anthocyanins resulting apoptosis in cancer cells [50–52]. Lately, anthocyanins have been shown to suppress angiogenesis through several mechanisms such as: inhibition of H2 O2 and tumor necrosis factor alpha (TNF-α)-induced VEGF expression in epidermal keratinocytes and by reducing VEGF and VEGF receptor expression in endothelial cells [53]. Angiogenesis is the physiological process of forming new blood vessels from the existing vascular network for the growth and metastasis of malignant tumors. The process of angiogenesis is controlled by multiple cytokines, of which the most important factor is vascular endothelial growth factor (VEGF); therefore, inhibiting the receptor of angiogenesis vascular endothelial growth factor receptor (VEGFR) could inhibit the metastasis of tumors effectively [18]. Anthocyanins were found to inhibit cancer cell invasion by reducing the expression of matrix metalloproteinase (MMP) and urokinase plasminogen activator (u-PA), both of which degrade extracellular matrix as part of the invasive process and, by stimulating the expression of inhibitors, both of which counteract the action of MMP and uPA [54]. There are two main aspects of cancer cells that threaten patient's health and life: invasion and metastasis. Successful tumor cell extravasation is successful by facilitating degradation of the extracellular matrix barriers. The balance of activated proteases and their naturally occurring inhibitors determine the degradation of the basement membrane [55].
