Расторопши: семена ранней потенциальных
Induction of apoptosis by silymarin
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- Anti-angiogenic activity of silymarin
- Anti-metastatic activity of silymarin
Induction of apoptosis by silymarinApoptosis or programmed cell death that occurs in various physiological and pathological conditions is one of the hallmarks of cancer. Several phytochemicals that are known to inhibit NF-kB and AP-1 activation can suppress cell proliferation and sensitize cells to apoptosis induction. Studies have reported that silymarin exerts its anticancer effects by causing cell cycle arrest and inducing apoptosis in different type of cancers. Li et al [32] have shown that silymarin induces apoptotic cell death in CH11-treated human malignant melanoma A375-S2 cells by increasing the expression of Fas-associated proteins with death domain (FADD), a downstream molecule of the death receptor pathway followed by cleavage of procaspase-8 that induces apoptosis. In UV-irradiated human malignant melanoma A375-S2 cells, silymarin activated SIRT1, a cell survival protein, down-regulated Bax and poly(ADP-ribose) polymerase (PARP) expression with decreased release of cytochrome c and induced G2-M arrest [33]. Recently, our studies have shown that diastereoisomers from silymarin induce apoptosis by causing the cleavage of PARP, caspase 9 and caspase 3 and decreasing survivin levels in human prostate cancer LNCaP and 22Rv1 cells [13]. Similar results have also been seen in DU145 cells with inhibition of active Stat3. Silibinin synergies the growth-inhibitory effect of mitoxantrone, a topoisomerase II inhibitor in prostate carcinoma PC-3 cells by reducing cell viability with increased apoptosis [34]. Silymarin causes apoptosis in human K562 leukemia cells by inhibiting Akt activity associated with activation of caspases-9 and -3 as well as PARP cleavage [35]. We have also shown apoptosis induction by silibinin involving p53-caspase 2 activation and caspase-mediated cleavage of Cip1/p21 in bladder transitional-cell papilloma RT4 cells [36]. Silibinin also promotes apoptosis of human hepatoma HuH7 cells by down-regulating survivin and up-regulating activated caspase-3 and -9 [31]. It has been shown that dietary supplementation with silymarin inhibits 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats by increasing apoptosis and modification of cell proliferation [37]. Anti-angiogenic activity of silymarinAnti-angiogenic activity is one of the fundamental ways of the cancer treatment. The anti-angiogenic potential of silymarin has been demonstrated in various cancers. We have demonstrated that silymarin inhibits the growth and survival of human umbilical vein endothelial cells (HUVECs) by inhibiting capillary tube formation, and induction of cell cycle arrest and apoptosis together with a reduction in invasion and migration. The molecular events associated with these effects include an up regulation of Kip1/p27, Cip1/p21 and p53; mitochondrial apoptosis and caspase activation; down regulation of survivin and inhibition of Akt and NF-kB signaling; and matrix metalloproteinase (MMP)-2 secretion [14, 15, 18, 38]. Other studies have also demonstrated that silymarin decreases the secreted vascular endothelial growth factor (VEGF) levels in prostate DU145 and breast MCF and MDA-MB-468 cancer cells [26, 38]. Yang et al [39] have shown that silymarin/silibinin treatment up-regulates VEGF receptor (VEGFR-1(Flt-1)) gene expression but not kinase insert domain containing receptor (KDR) in EA.hy 926 cells. They also reported that silymarin/silibinin causes a dose-dependent decrease in the vascular density index in LoVo cells. Gallo et al [40] have shown that administration of silybin-phosphatidylcholine complex, IdB 1016, down-regulates VEGFR- 3 and up-regulates angiopoietin-2 in female nude mice bearing human ovarian cancer xenografts. Furthermore, our in vivo work has shown that silibinin inhibits microvessel density and inhibits VEGF secretion in prostate and lung tumors [14, 41]. The anti-angiogenic effects of silibinin have also been shown in terms of down-regulation of MMP2 and CD34 in human hepatoma cell lines. [31]. Together, these findings clearly suggest an anti-angiogenic efficacy of silymarin and silibinin in different cancers, which could be an additional important mechanism of their chemopreventive efficacy. Anti-metastatic activity of silymarinCancer metastasis, a primary cause of cancer death and which may complicate the clinical management, depends on the motility and invasiveness of cancer cells. MMPs play an important role in the invasion and metastasis of cancer cells. Silibinin at 100μM concentration inhibited invasion and motility of SCC-4 tongue cancer as well as A459 lung cancer cells by down-regulating MMP-2 and urokinase-type plasminogen activator (u-PA) and up-regulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and PAI-1 expressions [42, 43]. Moreover, in A549 lung cancer cells, silibinin inhibited MMP-2 and u-PA expression through reducing ERK1/2 and Akt phosphorylation, which in turn led to the reduced invasiveness of the cancer cells [43]. In human osteosarcoma MG-63 cells, silibinin inhibited u-PA and MMP-2 expressions, IL-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness [44]. Activated protein-1 (AP-1), a complex consisting of homo- or heterodimers of the members of jun and fos family of proteins, regulates the expression of several genes involved in malignant transformation. In particular, AP-1 is known to promote epithelial to mesenchymal transition of tumor cells that is considered as a key step in cancer metastasis. Our previous studies have shown that silibinin suppresses UVB-induced AP-1 and NF-kB activation in mouse skin models [18]. Recently, Lee et al [45] have reported that silibinin reduces PMA-induced invasion of MCF-7 cells through the specific inhibition of AP-1-dependent MMP-9 gene expression. These findings suggest that by suppressing the cancer cells invasion through the specific inhibition of AP-1-dependent MMP-9 gene expression, silibinin represents a potential anti-metastatic agent. Together, the anti-invasive as well as anti- metastatic potential of silibinin could be of great value in the development of a potential cancer therapy. жүктеу/скачать 2.54 Mb. Достарыңызбен бөлісу:
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