Эпигаллокатехин и рак
MECHANISMS OF ACTION OF GREEN TEA COMPONENTS IN BREAST CANCER
жүктеу/скачать 1.88 Mb.
|
- Бұл бет үшін навигация:
- Anti-angiogenesis
- Interaction with target proteins
- Inhibition of cell signaling pathways
- Inhibition of enzyme activities
- Induction of cell cycle arrest and apoptosis
- Effects on microRNAs
- Other potential mechanisms
MECHANISMS OF ACTION OF GREEN TEA COMPONENTS IN BREAST CANCERTo better understand the preventive and therapeutic activities of green tea components on breast cancer found in animal studies, substantial research has been conducted to uncover the mechanisms at cellular and molecular levels. Experimental studies collectively show that green tea components lead to wide range of responses in animal models or breast cancer cells. Anti-angiogenesisInduction of new blood vessel growth, known as angiogenesis, is required for tumor growth and metastasis[50]. Angiogenesis permits rapid tumor growth by providing an exchange of nutrients, oxygen, and paracrine stimuli to the tumor. A recent study showed that EGCG treatment reduced plasma VEGF levels over the control mice and the EGCG-treated tumor had lesser micro-vessels than the control tumor. The down-regulation of VEGF expression by EGCG was associated with the inhibition of HIF-1α and NF-κB activation[39]. Consistently, administration of polyphenon E, a standardized green tea extract, at concentrations of 20 ng/μL or greater significantly decreased the formation of vascular structures. In vivo, quantification of micro-vessel density also indicated that polyphenon E drastically reduced angiogenesis in a dose-dependent manner[51]. Another in vitro study showed that green tea extracts and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells[52]. Taken together, inhibition of VEGF transcription appeared to be one of the molecular mechanisms involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention. Interaction with target proteinsThe eight phenolic groups of EGCG can serve as hydrogen bond donors to many biomolecules. EGCG has been recently shown to bind with high affinity to several target proteins, including phosphoinositide 3 kinase (PI3K)[53],67-kDa laminin receptor[54], Ras-GTPase activating protein (GAP) SH3 domain-binding protein 1 (G3BP1)[55], Bcl-xL and Bcl-2[56], vimentin[57], Fyn[58], GRP78[59], 70 kDa zeta-associated protein (Zap-70)[60], insulin like growth factor 1 receptor (IGF-1R)[61] and so on. All these proteins have been demonstrated to be important for the inhibitory activity of EGCG in breast cancer cell lines or animal models. Inhibition of cell signaling pathwaysVEGF is the most significant regulator in the development of the vascular system and is commonly overexpressed in breast cancer. Green tea catechins, especially EGCG, inhibit tumor growth, proliferation, migration, and angiogenesis of breast cancer[39,52]. Overexpression of Her-2/neu, the second member of epidermal growth factor receptor (EGFR) family, has been seen in about 30% of breast cancers and was associated with poor overall survival. EGCG treatment reduces basal phosphorylation and constitutive activation of the Her-2/neureceptor[62,63]. Other investigators have demonstrated that EGCG blocks Wnt signaling through the HBP1 transcriptional repressor that was previously shown to inhibit Wnt signaling[64]. In addition, Bigelow and Cardelli have investigated the effect of EGCG on inhibition of the hepatocyte growth factor signaling pathway. The results showed that EGCG (0.3 mmol/L) could completely blocked phosphorylation of Met (HGF Receptor) and its downstream extracellular signal-regulated kinases 1 and 2 (ERK1/2), and Akt/protein kinase B (PKB)[65]. Inhibition of enzyme activitiesNumerous in vivo and in vitro studies have been published on the anti-tumour and anti-proliferative properties of green tea. EGCG has been reported to inhibit a number of enzymes. For example, Liang et al[66] showed that cyclin-dependent kinase (CDK) 2 and CDK4 were inhibited by 30 μmol/L EGCG in MCF-7 breast cancer lines, and this was associated with cell cycle arrest in G0 and G1. Also, EGCG increased the expression of the CDK inhibitor p21 in human breast carcinoma cells. Another study found that EGCG inhibited p38-regulated/activated protein kinase (PRAK; IC50 = 1 μmol/L) and dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A; IC50 = 0.33 μmol/L), but did not inhibit CDK2[67]. A recent study shows that EGCG is an ATP-competitive inhibitor of both PI3K and mammalian target of rapamycin with Ki values of 380 and 320 nmol/L, respectively[53]. Induction of cell cycle arrest and apoptosisDysregulated cellular proliferation and apoptosis are a hallmark of cancer. Green tea extracts and EGCG are capable of inhibiting cell growth and inducing apoptosis via a variety of mechanisms. Recent studies showed that EGCG suppressed proliferation and growth of triple negative breast cancer Hs578T cells[68], estrogen and progesterone receptor positive human breast cancer cells[69], MMTV-Her-2/neu mammary gland tumor NF639 cells[63] and others[70]. Also, EGCG induced apoptosis in estrogen receptor negative MDA-MB-468[71] and MDA-MB-231 cells[72]. Therefore, it is likely that EGCG induces cell cycle arrest and apoptosis in most, if not all, breast cancer cell lines. EGCG increases protein expression of p21 and p27[73]. Green tea inhibited expression of Ki-67 in both benign and malignant cells[74]. EGCG alters the activity of EGFR and its downstream targets[75]. In addition, research showed that catechin hydrate increased the expression of pro-apoptotic genes caspase-3, -8, and -9 and TP53[70,76]. In addition, EGCG can mediate the retinoblastoma (pRb)-E2F/DP pathway, an important regulator of cell cycle arrest and apoptosis[77]. Effects on microRNAsMicroRNAs (miRNAs) are small (about 22 bases), single stranded, endogenous, noncoding RNAs that negatively regulate the translation and/or stability of mRNAs. It could be affected by EGCG to cause subtle changes in multiple molecular targets and pathways. In 2010, the first global miRNA expression profile showed that there were 16 down-regulated and 7 up-regulated miRNAs in MCF-7 breast cancer cells treated with Polyphenon-60 green tea extract[78]. Remarkably, among the miRNAs down-regulated by Polyphenon 60 treatment, MiR-27a was the most dramatic[78]. MiR-27a directly targets FOXO1, a putative tumor suppressor, and regulates endogenous protein expression in MCF-7 breast cancer cells[79]. In addition, Jang et al[42] found that EGCG up-regulates MiR-16 in tumor cells, which down-regulates IκB kinase α and subsequently induces IκB accumulation in tumor associated macrophages, and inhibits M2 polarization. These studies suggest that the ability of green tea components to regulate miRNA expression may be one of potential mechanisms for green tea in breast cancer prevention and treatment. Other potential mechanismsIn addition to mechanisms discussed above, there were other mechanisms involved in anticancer effects of green tea components including DNA methylation, metabolism, endoplasmic reticulum stress response and so on. Treatment of breast cancer cells with EGCG results in promoter demethylation of human telomerase reverse transcriptase, retinoic acid receptor β2 and target of methylation-induced silencing 1[80,81]. These studies demonstrated that EGCG has the potential to reverse epigenetic changes. A pilot study in overweight breast cancer survivors showed that intake of decaffeinated green tea for 6 mo was associated with a slight reduction in body weight and improved high-density lipoprotein and glucose homeostasis[82]. Also, EGCG treatment inhibited the expression of fatty acid synthase in MCF-7 and AU565 human breast cancer cell lines by blocking heregulin[83]. And our studies showed that EGCG potentiates quercetin-, taxol- and vinblastine-induced activation of pro-apoptosis arms of the endoplasmic reticulum stress response, such as JNK phosphorylation, caspase-7 and poly (ADP-ribose) polymerase (PARP) cleavage[47,84,85]. In addition to these mechanisms discussed in breast cancer, there are other multiple mechanisms presented in colon, lung, prostate, ovarian and other cancers. It can be expected that further in-depth research on each of these specific mechanisms will uncover more details of the action of green tea in breast cancer prevention and therapy Проведение Химиопрофилактики устного рака: зеленый чай с опытом. Оральный рак имеет хорошо характеризуется переход от оральных предраковых эпителиальных изменений к инвазивным раком, делая устные плоскоклеточная карцинома оптимальный болезни для химиопрофилактики вмешательств до злокачественной трансформации. Основной целью химиопрофилактики вот обратное, подавлять или сдерживать прогрессирование предраковых поражений до рака. Из-за длительного перорального патогенез, ее проведение химиопрофилактики с использованием натуральных продуктов был найден перспективный из-за их уменьшении дозы и ограниченные профили токсичности. Этот обзор обсуждает с акцентом на клинические испытания с использованием экстракта зеленого чая (GTE) в проведение химиопрофилактики оральных предраковых поражений наряду с использованием ГТД как химические агента в различных других видов рака, а также. Стоит включить экстракт зеленого чая в устной программы скрининга для оценки предраковых поражений сравнивая результаты между обработанной и необработанной группе. Учитывая широкое признание зеленого чая, его преимущества могут помочь в эффективной химиопрофилактики устного рака. J Nat Sci Biol Med. 2014 Jan;5(1):3-7. doi: 10.4103/0976-9668.127272. жүктеу/скачать 1.88 Mb. Достарыңызбен бөлісу:
|