Discursive Essay on Antiproliferative Action of EGCG on Pancreatic Cancer Cells

Discussion

Cancer is described as a disease that is characterized by excessive proliferation of cells and of their inability to die. Normally, cells can kill themselves in a balanced process known as ‘apoptosis’. It is becoming clear that too little cell suicide by apoptotic process can lead to a variety of cancers, including pancreatic cancer. Further investigation suggested that EGCG has Antiproliferative action on pancreatic cancer cells and this Antiproliferative action is mediated through Programmed cell death or apoptosis. Although some studies indicate that the antiproliferative action of EGCG in pancreatic cancer was never investigated. More importantly, the present study unravels the involvement of mitochondria in the EGCG-induced apoptosis of pancreatic cancer cells. The novelty of our studies is the differential response of different pancreatic cancer cell lines to tea polyphenol. Thus, it would be of value to develop biomarkers of resistance in the course of mechanistic studies and to develop a sense of resistant phenotype. Studies are in progress in the laboratory to understand the mechanism of different sensitivities of pancreatic cancer cell lines to EGCG. The results of our studies involving pancreatic cancer are quite concordant with the previous observation implying that a direct inhibition of antiapoptotic Bcl-2 family proteins (1,2) except the necessity of higher concentration of EGCG in pancreatic cancer cells. The inhibition of Bcl-2 by EGCG might result in an up-regulation of pro-apoptotic member Bax. In addition, we noted an oligomerization of Bax along with cytochrome c release/change in the mitochondrial membrane potential in EGCG-treated cancer cells. The requirement of high concentration of EGCG to suppress cell proliferation or to induce apoptosis in pancreatic cancer cells might be due to the difference in the cell permeability of EGCG or sequestering of EGCG by other proteins yet to be identified. A previous study by Takada demonstrated the suppression of growth inhibition as well as invasion of pancreatic cancer cells, at 0.1--0.2 µM concentration of EGCG. Treatment with 0.2 µM EGCG resulted in suppression of the growth of PANC-1 (15.4%) and MIA PaCa-2 (26.0%) cells. It is to be noted that a 0.1 mM concentration of EGCG is often required to trigger stress signals in cancer cells. The prevention of EGCG-mediated apoptosis by JNK inhibitor II suggests the involvement of ROS-mediated JNK activation in this pathway. The ROS comprises of singlet oxygen, hydroxyl radicals, superoxide, hydroperoxides, and Peroxides. We have noted an increase in the hydrogen peroxide level owing to EGCG exposure as noted in the case of lung cancer cell lines have indicated that JNK signalling is necessary for the stress-induced release of cytochrome c release and programmed cell death. JNK signalling and cytochrome c release may be interlinked to a pro-apoptotic member of Bcl-2 family because activated JNK is unable to evoke apoptosis in cells deficient of Bax. Our observation indicates that the concerted efforts of JNK activation and Bax oligomerization might play a pivotal role in the demise of pancreatic cancer cells. At present, two major pathways that link apoptosis have been identified: (a) intrinsic or mitochondrial and (b) extrinsic or death receptor-related. The intrinsic pathway involves the cell sensing stress that triggers the mitochondria-dependent processes, resulting in cytochrome c release and activation of caspase-9. EGCG-induced apoptosis in some cancer cells might be orchestrated by the cooperative effects of both ‘extrinsic’ and ‘intrinsic’ pathways. To summarize, our data suggest that EGCG initiates the cell death process through cell cycle arrest at an earlier phase, as well as the oligomerization of pro-apoptotic regulator Bax, in pancreatic cancer. Perhaps, oligomeric Bax along with other pro-apoptotic members (Bak or Bid) form pores in the mitochondrial membrane to facilitate the release of apoptogenic factors from the mitochondria to cytosol. The permeabilization of the outer membrane is thought to be a major event in releasing proteins such as cytochrome c from the intermembrane space. Indeed, EGCG-induced apoptosis in pancreatic cancer cells is accompanied by the mitochondrial membrane depolarization and the release of cytochrome c from mitochondria into the cytosol. Cytochrome c is bound to the outer surface of the inner membrane phospholipids, primarily to cardiolipin molecules. Mechanistically, it is possible that ROS generation in mitochondria targets membrane lipid cardiolipin to dissociate cytochrome c. In pancreatic cancer cells as observed here, EGCG-mediated ROS production might play such a role. In a variety of cell types, the apoptosis triggering effects of ROS were noted in vitro. The very poor prognosis and high mortality that pancreatic cancer patients face results, in part, from our current inability to both identify individuals at increased risk for this disease and detect neoplasms earlier. The elucidation of the mechanism by which the existing chemopreventive agents decrease pancreatic tumor growth should facilitate the establishment of efficacious regimens for the inhibition of human pancreatic carcinoma. Apoptosis in EGCG-exposed pancreatic cancer cells might hold future promise for deploying green tea as a chemopreventive agent. The development of a chemopreventive agent in regular diet is very promising for pancreatic cancer since this spiteful form of human malignancy is often diagnosed very late. Thus, the induction of the cell death program by the polyphenol constituent of green tea might be helpful in evading the potential malignant outcome of genomic damage in pancreatic cancer.

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Conclusion

Chemoprevention, also defined as ‘‘slowing the process of carcinogenesis’’ is a concept that appears to be a viable option in control. To be effective in preventing cancer. Chemopreventive intervention should be addressed during the early stages of the carcinogenesis process. A plethora of experimental evidences suggest that a change in dietary and lifestyle factors prevents the Chronic inflammation and/or oxidative stress. Within the chemopreventive armamentarium, the use of natural agents from dietary sources is generally preferred with respect to bioactive molecules deriving from other sources. Many of these natural occurring agents demonstrate antioxidant activity, and compounds belonging to polyphenols chemical class may play a promising role in cancer prevention. Epidemiological studies conducted in humans supported the existence of an association between natural polyphenols consumption and a decrease in cancer rate. In the last decade, a representative member of polyphenols, i.e. EGCG, has been the focus of a number of studies scrutinizing its beneficial effects on health. Therefore, consumption of green tea has become more and more popular in the world due to its versatile health benefits. However, despite its neoplastic properties, EGCG presents important pharmacokinetic problems, due to inefficient systemic delivery and bioavailability. In order to improve the poor systemic bioavailability and cellular uptake of EGCG, various strategies have been adopted, which include combination therapy or polytherapy that consumes EGCG with one or more medications. In addition, recent studies conducted implying both EGCG and CSCs to found that EGCG induces multiple of anticancer effects in CSCs and enhances the chemo-sensitivity of chemo-drugs in CSCs. In this review the current available studies of the anti-cancer effects of EGCG alone and combined with other dietary and pharmaceutical agents as well other approaches used to deliver sustained levels of EGCG have been covered and discussed in order to introduce some furnish driving force for further evolution of research on innovative database able to consolidate the chemopreventive potential of EGCG.

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