Overview of Applications to Flavonoids to Cancer

Overview of Applications to Flavonoids to Cancer Flavonoids and its effect on the proliferation of the cells: Published date suggested that flavonoids have capability to inhibit phosphate protein kinases on their specific sites. Flavonoids interact with Akt/PKB (protein-kinase B), tyrosine kinase P1KC (protein-1 kinase C), PI3-kinase (phosphoinositide 3-kinase), and MAP (mitogen-activated protein) kinase signaling pathways. Flavonoids have been reported to activate and inhibit the effects on these signaling pathways by modulating of their gene expressions (Williams et al., 2004). Flavonoids inhibitory mechanism has been proved by altering their receptor phosphorylations or blocking growth factor receptor binding. Flavonoids also inhibit Fyn and Lck protein kinases, involved in T cell signaling transport (Calic et al., 2005). PI3K catalyze productions of PIP1 and PIP2. PIP3 may activate the PDK1 which stimulates the Akt/PKB. Of these effects PDK1 is essential for regulator of cell growth, proliferation, differentiation, migration and apoptosis. Bad, Bcl-2, and caspases proteins are responsible for apoptosis, these can be inhbitied by Akt pathway. Several data have been suggested that flavonoids directly inhibit the PI3K pathway by their interacting their ATP binding sites. MAPK pathway ((ERK2, JNK1 and p38) are responsible for releasing of many survival genes (c-Fos, c-Jun) and those genes which are involved in the antioxidant activity (detoxification enzymes, glutathione S-transferase, glutathione-reductase) have also been activated by low level of quercetin. Anti-cancerous properties of the flavonoids: Flavonoids also have anticancer activities by blocking their cellular mechanism. Flavonoids targets the cell cycle regulator proteins (cycline-dependent kinases and their inhibitors, protein p53 and Rb, E2Fs, ATM/ATR and surviving transition-controlling points G1/S and G2/M) (Sing et al., 2006). Flavopiridol properly inhibits the CDK1-and CDK2 cell regulating pathways (Vermeulen et al., 2003). Cell proliferation and cell viability ratio of the prostate cancer decreased with treatment of quercetin. Quercetin induced apoptosis with down-regulating mechanism of Hsp90 expression of proteins, resulting in the death of cancer cells by inhibiting the cellular growth. (Aalinkeel et al., 2008). Inhibiting cellular growth and DNA synthesis and blockage of cell cycle at S-phase in squamta cells have been reported with quercetin (Haghiac et al., 2005). Querecetin also prevents growth of nasopharyngeal cancer cells via arrest of cell cycle at G1/S phase (Ong et al., 2004). ERK (extracellular signal-regulated kinase) pathway stimulates the lung cancer which is derived from the A549 cell proliferation have been reported combine inhibitory effects of querecetin and kaempferol (Hung et al., 2007). Quercetin stimulates the protein expressions of p21 and p22 which inhibited the cell cycle in H epG2 cells (Mu C et al., 2007). Quercetin at the concentration of (248uM) down-regulates the mutantp53 expressions which is almost untraceable in the cell lines of the breast cancer. Negative control was too lower as compare to normal gene p53. Quercetin at the dose of 70 uM, having inhibiting activity on cell division, and trysine kinase activity, is an enzyme placed on the cell membrane and is involved in growth factors and signaling transduction in nucleus (Lamson et al., 2000). Scientific data have been reported that flavonoids especially the quercetin having oral anticancer properties. Quercetin inhibits the cellular growth and DNA synthesis depending the dose and timing of the administration. Quercetin induced apoptosis with treatment of caspase-3 proteins after 72 hours, and cell necrosis after 24-48 hours in SCC-9 cells. Flow cytometer studies confirmed cell cycle blockage at S-phase with the treatment of quercetin (Haghiac et al., 2005). Quercetin induced cell proliferation of B16-BL6 after 72 hours and also caused apoptosis in B16-BL6 cells and reduced the expressions of Bcl-2 and anti-apoptotic proteins (Zhang et al., 2000). Anti-apoptotic properties of the flavonoids: Flavonoids have been reported to induce apoptosis process by activating and modulating cellular signaling pathways resulting in death of pre-cancerous and maligne cells, which terminates cancer development or progression. Human prostate cancer cell line LNCaP, treated with different concentrations of quercetin shown to inhibited cell death after 24 hours. Inhibition of Akt survival signals have been activated in the treated cells. Rapid decrease in Ser 136 phosphorylation in Bad that is a Akt target have been reported with treatment of LNCaP and 100 uM of quercetin. Quercetin have been shown to reduce the Bcl-XL, Bx ratio and enhances translocation and multimeriation of Bax in the mitochondrial membrane; cytochrome-c released by translocation, and the caspase 3, 5, 9 proteins and PARB (poli(ADP-ribose)polymerase). Remarkably, quercetin does not induce cellular viability or apoptosis at same concentrations in normal prostatic epithelial cells (Zhanget al., 2000). Exposure of cells for longer time on quercetin induced apoptosis intervened by reduction of thymidylate synthase (Ong et al., 2004). Quercetin induced apoptosis in CNE2 and HK1 cells after 24 hours of treatment and treatment was continued when necrosis was observed. HeLa cells have been exposed on non-toxic flavonoid concentrations which slightly susceptible to TRAIL induced cell death. TRAIL mediated cytotoxicity in HeLa cells was increased by apigenin and ginstein but no effect have been documented with kaempfeol and quercetin (Leeet al., 2008). Luteoline induced cell cytotoxicity by suppressing PI3K/Akt (phosphattidylinositol 3-kinase), NF-kB (nuclear factor kappa B) and XIAP (X-linked inhibitor of apoptosis protein) and activates of apoptotic pathways, such as p53 protein (Lin et al., 2008 and Lopez-Lazaro., 2009). At high doses majority of the flavonoids suppressors AP-1 activity (activator protein 1) by MAPK (mitogen – activated protein kinase) pathway (Gopalakrishnan et al., 2006). Activation of cellular signaling pathways in cancer and flavonoids: Figures-9. Sources of inflammatory mediators and their origin Figure-7. Some diseases and cancers associated with reactive oxygen species (ROS) Conclusion: Oxidative stress brings the changes into the cells resulting in gene mutation which leads to the carcinogenesis. It brings direct or indirect intra and inter-cellular and intercellular transduction and transcription changes by antioxidants. The role of oxidative stress in carcinogenesis and tumor bearing conditions is complex and various mechanisms and substances are involved. Clinical evidence suggests that oxidative stress and inflammation linked to free radicles over generation may be the key factor in development of chronic diseases, insulin resistance, diabetes, cardiovascular and other diseases. Excessive nutrition, stress in combination with sedentary lifestyle, can independently result in overburden of glucose and fatty acid accumulation with musle, adipose tissue and pancreatic cells. All these factors lead to chronic inflammation resulting in chronic diseases. Published data suggested that the key role of polyphenolic compounds such as flavonoids as therapeutics agents in the inflammatory diseases including obesity, T2DM, cardiovascular diseases, neurodegenerative diseases cancer and aging. Flavonoids are the key modulators of inflammatory molecules. Flavonoids inhibits the AMPK one of the major pathway of inflammation and cancer. Activation of AMPK by flavonoids causes to increase the cancer cell apoptosis, inhibit cell proliferation and some studies suggested that it a neoplastic agent Furthermore, inflammation stimulates various inflammatory mediators, chemokine’s, cytokines, signaling transductions and transcriptional factors; overproduction for long periods may lead to chronic inflammation which in turn to chronic diseases such as neurological diseases and cancer. Better clarification of these mechanisms will be beneficial to the development of efficacious prevention and therapies of inflammation associated cancers. Moreover, effects of flavonoids at molecular mechanism and study also should be carried out on modulatory action; effects on transcription levels of the flavonoids should be studied. Fig-4. Anti-inflammatory activities of the flavonoids SOD- Superoxide dismutase 2- CAT- Catalase 3- GPx- Glutathione peroxidase 4- GR- Glutathione reductase 5- GST- Glutathione S-transferase. 6- ÃŽ ³GCS- ÃŽ ³-glutamylcysteine synthetase 7- NADPH:NQO1- quinone oxidoreductase-1. 8- HSP70- heat shock proteins. 9- MPO- myeloperoxidase 10- iNOS- inducible nitric oxidase synthase. 11- OH Hydroxyl radical. 12- O2 -superoxide radical. 12- MDA- Malondialdehyde 13- IL-2 interlukins-2 14- FMLP- Formyl-Methionyl-Leucyl-Phenylalanine. 15- TNF-ÃŽ ±- Tumor necrosis factor ÃŽ ±. 16- LTB4- Leukotriene B4. 17- LTC4- Leukotriene C4. 18- TXB2- Thomboxane B2 19. PGE2- Prostaglandins e2. 20- NF-ÃŽ ºB- Nuclear Factor Kappa Beta 21- ICAM-1- Intercellular Adhesion Molecule 22- VCAM-1- vascular cell adhesion molecule-1