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Cellular signaling in cancer
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- 3. Anticarcinogenic activity
2. Cellular signaling in cancerCancer development (i.e. carcinogenesis) is generally recognized as a complex and multistep process in which distinct molecular and cellular modifications occur. In order to simplify understand the different possible options for chemoprevention and chemotherapy in cancer development and progression, three well defined stages have been described: (i) initiation is a rapid phase, comprises the exposure or uptake and interaction of cells, especially DNA, with a carcinogenic agent, and its distribution and transport to organs and tissues where metabolic activation and the covalent interaction with target cell DNA occur, leading to genotoxic damage, (ii) promotion is considered a relatively and reversible process in which actively proliferating abnormal cells persists, replicates and may originate a focus of preneoplastic cells, and (iii) progression stage is the final phase of neoplastic transformation, an uncontrolled growth of the cells (tumor) occurs, involves the gradual conversion of premalignant cells to neoplastic ones with an increase of invasiveness and metastasis potential, and new blood vessel formation (angiogenesis) [19]. The transcription factors, such as NFκB and AP-1, are transiently activated to regulate target gene expression in response to extracellular stimuli through specific intracellular signal transduction pathways [10]. Because advanced metastasized cancers are mostly incurable, an effort to prolong or block the process of carcinogenesis through chemoprevention has become an important and feasible strategy for cancer control and management. Inhibition of oxidative damage constitutes the first line of defense system against carcinogenic insults and can be considered as most effective way for preventing cancer. It can be achieved by scavenging the reactive oxygen species (i.e. •OH and O2•-) or by inducing their detoxification through induction of phase-II conjugating enzymes (GST, glucuronidases and sulphotransferases) [5, 20]. Antioxidant enzymes (CAT, SOD, GPx and GR) are important components of the cellular stress response whereby a diverse array of electrophilic and oxidative toxicants can be removed from the cell before they are able to damage target cell DNA. In the tumor promotion step, mechanisms that stop or slow down cell division could be potentially beneficial (induction of cell cycle arrest, and apoptosis) in order to restore the lost balance between cell proliferation and apoptosis [21]. At the latest phase of carcinogenesis (progression), the interruption of angiogenesis or the prevention of malignant cells to escape from original location and invade other tissues could also be potentially useful. During all the stages of cancer development many key proteins related to cellular antioxidant defences (e.g. SOD, CAT, GST, GPx and GR), cellular proliferation and survival transduction pathways (e.g. AKT, PI3K, MAP kinases, and NFκB) are upregulated, and anti-apoptotic members of Bcl-2 family genes (e.g. Bax and Bak), and tumor suppressor genes (p53, BRAC1 and BRAC2) are downregulated [13]. Center to the cancer biology is disrupted intracellular signaling cascades, which transmit aberrant signals resulting in abnormal cellular functions. Consistent with this notion, targeting deregulated intracellular signaling cascades is considered to be a rational approach in achieving chemoprevention. Recent studies have shown that EGCG cancer chemopreventive agent exerts its effect by modulating one or more cell signaling pathways in a manner that interrupts the carcinogenic process [22]. Moreover, tea flavonoids display a vast array of cellular effects, they can affect all stages of cancer development by up- or down-regulating multiple key cellular proteins involved in diverse cellular signal transduction pathways: proliferation, differentiation, apoptosis, angiogenesis or metastasis, resulting in a potential beneficial effect [4, 23]. The potential chemopreventive effect of EGCG seems to be quite specific, and cancer cell lines appear to be more sensitive than normal cells, since EGCG has shown higher cytotoxicity in cancer cells than in their normal counterparts. The inhibition of lung tumor in A/J mice by EGCG was associated with decreased cell proliferation, induced apoptosis, and decreased angiogenesis as well as with lower levels of phospho-c-jun and phospho-ERK1/2 in lung adenomas and carcinomas [24].
Procarcinogens such as N-nitrosodiethylamine and aflatoxins that are activated by cytochrome P450 enzymes are able to modify DNA and induce tumorigenesis [30]. Tea flavonoids can directly neutralise the procarcinogens by their strong antiradical activity, before cell membrane injury occur. EGCG exhibits the highest protection against DNA scissions, mutations, and in non-enzymatic interception of superoxide anions. Many animal studies indicate that EGCG can inhibit the growth of malignant cells and induce apoptosis even in cancerous cell lines resistant to CD95-mediated apoptosis. Some results suggest that EGCG induce apoptosis due to their pro-oxidant effect. In a study where EGCG has been tested on oral cancer cell lines along with curcumin, EGCG blocked cell division in G1, whereas curcumin blocked cell division in S/G2M. EGCG has antiproliferative activities on tumor cells through the blockage of growth factor binding to the receptor and the suppression of mitogenic signal transduction [31]. Volatiles in tea have been found to be moderately cytotoxic against human carcinoma cells, with β-ionone and nerolidol exhibiting the strongest activity [32]. EGCG blocks urokinase, an enzyme which is essential for cancer growth and metastasis formation, by interfering with the enzyme’s ability to recognize its substrates [33]. EGCG can also kill specifically transformed cells by adenovirus [13]. Tea catechin EGCG inhibits DNA synthesis of rat hepatoma cells, leukemia cells and lung carcinoma cells [15]. EGCG, in a transgenic mice model for skin cancer, has exhibited a preventive effect and/or improvement of the situation [34]. Sazuka et al. [35] reported that the adhesion of lung carcinoma cells to fibronectin, a plasma protein, can be inhibited by EGCG, hindering cancer progression. It has been known that immune cells play an important role in host defence against tumor development and progression. Their plasma membranes are rich in polyunsaturated fatty acids, and are thus susceptible to oxidation by ROS [36]. Besides their antioxidant activity, flavonoids exhibit a modulating effect on cells responding to a stimulus or antigen-activated cells, like mast cells, lymphocytes, macrophages, platelets, hepatocytes, and smooth muscle [15]. The TNF-α is a cytokine induced by tumor promoters that stimulates the production of cell adhesion molecules and the inflammatory process response [23]. EGCG inhibits NFκB and expression of TNF-α, reduces cancer promotion [28]. The activation of immune B cells involved in antibody production induces the phosphorylation of tyrosine residues of proteins implicated in cancer cell proliferation. EGCG selectively inhibits the tyrosine phosphorylation in the intracellular transduction pathway and the spheroid and colony formation in vascular smooth muscle cells [37]. Antioxidant molecules, flavonoids inhibit the expression of the multi-drug resistance gene and modulate topoisomerase activity associated with tumor growth. It is evident that tea flavonoid EGCG exhibits many protective activities and different metabolic pathways are involved [15]. It acts as strong ROS scavenger and antioxidant, selectively inhibit specific enzyme cancer developing activities such as DNMTs, and repair DNA aberrations [25]. Further research is needed for a better understanding of effect of EGCG at the cellular and molecular levels of the complex processes of cancer development and inhibition. Then it will be possible to explain how EGCG promotes cancer prevention and inhibition. жүктеу/скачать 1.88 Mb. Достарыңызбен бөлісу:
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