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- BROAD SPECTRUM CANCER CHEMOPREVENTIVE EFFICACY OF SILIBININ
SILIBININSilibinin (Fig. 1a) is derived from the seeds (Fig. 1b) of milk thistle (Silybum marianum; Asteraceae) which has its origins in the Mediterranean region where for millennia it has been used as a remedy for a variety of ailments, particularly of the liver, gall bladder, and kidneys. More recently, milk thistle has been found to be effective in treating hepatic injury due to bile duct inflammation, cirrhosis, fatty liver, mushroom poisoning, and viral hepatitis (16). Perhaps as a consequence of this longstanding medicinal use, the characteristic purple-red flowers of the milk thistle (Fig. 1c) can now be found growing worldwide. In modern times, the usage of the whole milk thistle has been supplemented with a standardized extract of milk thistle seeds called silymarin. This extract is composed of a complex mixture of several flavonolignans and other compounds. The flavonoid silibinin is the principle active ingredient found in silymarin and is by far the most abundant component, along with the stereoisomers dihydrosilybin, isosilybin, silychristin, and silydianin. Silibinin, in turn, is composed of an approximately equimolar mixture of two diastereomers (silybin A and silybin B). As a polyphenolic compound, silibinin is fairly water insoluble and thus is often administered within capsules. Once in the GI tract, silibinin is absorbed, circulated, conjugated in the liver, and excreted, much of it in the bile (17). In mice, plasma concentrations of free silibinin peak at 30 min and in tissues at 60 min, whereupon it decays with a half-life of 57 to 127 min; however, the concentrations of conjugated silibinin peak at 1 h and decay with a half-life of 45 to 94 min (18). Silibinin exhibits low toxicity as reported in studies where animals were intravenously injected with silymarin. A 50% lethal dose (LD50) required high concentrations of silymarin, depending on specific experimental conditions: mice tolerate 400–1,050 mg/kg, rats 385–920 mg/kg, and rabbits and dogs 140–300 mg/kg (19–21). When silymarin was delivered orally, the required values of silymarin to achieve toxicity were, in some cases, over 10 g/kg (19–21). In two human trials, a commercial silibinin formulation, silibinin phytosome, was administered orally to prostate cancer patients at 13 g daily for a mean of 20 days and 2.5–20 g/daily for 28 days, respectively (22,23). Consistent with silibinin’s target organ in clinical usage, the most common adverse event at high doses was asymptomatic hepatotoxicity followed by low-grade hyperbilirubinemia (grades 1–2) and diarrhea (22,23). There was one case of a grade 4 postoperative thromboembolic event (out of 19 total treated patients within the two trials). Together these studies provide compelling evidence for well-tolerated administration of high doses of silibinin in human patients. BROAD SPECTRUM CANCER CHEMOPREVENTIVE EFFICACY OF SILIBININFlavonoids possess antioxidant activity which has been reported to result in diverse biologically protective properties such as inhibiting inflammation, neoplasia, hepatic injury, and other ailments (24). Consistent with other flavonoids, silibinin has been found to be a very potent antioxidant, buttressing native cellular antioxidant mechanisms such as glutathione (GSH) and superoxide dismutase by scavenging free radicals, and reactive oxygen species (ROS) (25,26). This may in part explain silibinin’s effectiveness in addressing hepatic injury whether as a result of disease or exposure to toxins as this anti-oxidant activity may eliminate the oxidative stress associated with hepatic insults preventing the induction of lipid peroxidation (and thus cell death). As a consequence of the general anti-cancer properties associated with flavonoids collectively, as well as the strong antioxidant potential of silibinin specifically, there has been significant interest in adapting silibinin for use as a chemopreventive agent. In fact, silibinin has been widely investigated for anti-cancer efficacy in a broad range of cancers models. Based on these factors, and the diseases silibinin has been historically used to treat, it is perhaps not a surprise that silibinin has been found to have an inhibitory effect on cancers of several digestive and excretory organs. Silibinin was found to inhibit cell proliferation and invasion in various hepatocarcinoma cell lines (27–30) as well as in a mouse xenograft model (31). These effects appear to be a consequence of inducing apoptosis as well as cell cycle arrest in hepatocarcinoma cells. Silibinin inhibited ERK1/2 signaling, downregulated survivin, highly expressed in cancer protein-1, the E2F1/DP1 complex, cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)2, and CDK4 levels and induced CDK inhibitor (CDKI) Kip1/p27 in hepatocarcinoma HEPG2 cells (27,28). Furthermore, silibinin altered Akt signaling, downregulated phosphorylation of retinoblastoma (Rb), upregulated histone acetylation, and activated caspases 3 and 9 in hepatoma HuH7 cells (30). In addition, silibinin reduced vascular endothelial growth factor (VEGF) secretion, metalloproteinase-2 (MMP-2), and CD34 in hepatic cancer cells suggesting inhibition of angiogenesis in hepatic tumors (29,30). In pancreatic cancer cell lines, silibinin inhibited their proliferation in a dose- and time-dependent fashion which translated to a decrease in tumor volume in a mouse xenograft model (32). Again, this inhibition appeared to be a function of both increased apoptosis as well as cell cycle arrest by silibinin. In gastric cancer cells, silibinin dose-dependently inhibited TNF-α-induced secretion of metalloproteinase-9 (MMP-9) (33). Silibinin was found to be deliverable to the human colorectal mucosa in high amounts through ingestion of nontoxic doses of silibinin (34), and consistent for use as a chemopreventive agent, silibinin was found to be beneficial in early colon tumorigenesis (35), reducing loss of differentiation of carcinomas in mice (36), while also inhibiting colon cancer stem-like cells (37). Silibinin potently inhibited the growth of HT-29 and LoVo cells both in vitro as well as in xenograft models, strongly inducing G1 and more modestly G2-M cell cycle arrest (38,39). This was associated with decreased levels of cyclins (A, B1, D1, D3, and E), cell division cycle 25C (cdc25C), and Cdc2/p34; decreased activity of cyclin-dependent kinases (1,2,4,6); and phosphorylated Rb in conjunction with increased levels of CDKIs (Cip1/21 and Kip1/p27) (38,39). Silibinin also induced apoptosis associated with increased activation of caspases 3 and 9 as well as poly(ADP-ribose) polymerase (PARP) in LoVo cells (38); however, silibinin-induced apoptosis was independent of caspases activation in HT-29 cells (39). Furthermore, the invasive potential of LoVo cells was reduced by silibinin which was associated with a decrease in MMP-2 (40). Silibinin treatment also led to a decrease in polyp size and number in APCmin/+ mice, a model of familial adenomatous polyposis (41,42). This phenomenon was associated with decreased β-catenin, c-Myc, phospho-glycogen synthase kinase-3β, and phospho-Akt (41,42). Silibinin-mediated reduction in colorectal carcinoma proliferation and concomitant increase in apoptosis were associated with inhibition of ERK1/2 and Akt (43). Silibinin-mediated angiogenesis inhibition was associated with decreased VEGF, cyclooxygenase (COX), hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), nitrotyrosine and nitrite levels, and an increased VEGFR-1 (Flt-1) expression (41,43–45). Silibinin inhibited CDK8 and β-catenin signaling which inhibited SW480 tumor growth (46) and initiated an autophagic-mediated survival response in SW480 and SW620 cells (47). Silibinin also suppressed 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rat models via modulating xenobiotic metabolizing enzymes and increasing enzymatic antioxidants to detoxify carcinogens (48,49). This action translated to decreased oxidative stress and subsequent lipid peroxidation, abrogating DMH-induced neoplasia (50). Consistent with its effect in models of digestive organ cancers, silibinin was also found to inhibit excretory organ cancers. Silibinin treatment decreased renal cancer 786-O cell proliferation and invasiveness (51), while inhibiting proliferation and increasing apoptosis in renal cancer Caki-1 cells (52). This action was associated with inhibition of epidermal growth factor (EGF), ERK1/2, and survivin expression with concomitant upregulation of p53 expression and caspase cleavage (52). Silibinin feeding reduced the size of 786-O renal tumors in mice xenografts which was associated with decreased expression of MMP-2, MMP-9, and urokinase-type plasminogen activator (u-PA), and activation of p38 and ERK1/2 (51). Silibinin also enhanced the sensitivity of −786-O renal cell carcinoma cells towards 5-fluorouracil and paclitaxel (51). Treatment of SN12K1 cells with silibinin reduced cell viability and DNA synthesis resulting in apoptosis (53). Likewise, silibinin-fed SCID mice injected with SN12K1 cells exhibited a reduction in tumor size (54). Consistent with these results, several studies have shown that silibinin inhibits growth as well as induces apoptosis in several urinary bladder cancer cell lines which were associated with an increase in p53 expression, downregulation of survivin, cyclin D1, ERK1/2 phosphorylation and nuclear phospho-p65, cleavage of caspases, PARP, and Cip1/p21, and mitochondrial release of cytochrome c, Omi/HtrA2, and apoptosis-inducing factor (55–60). This silibinin-mediated inhibition was also observed in rat models of urinary bladder cancer reducing lesions (60). Silibinin was also found to reduce oral cancer cell invasion as a consequence of decreased MMP-2 and u-Pa expression, decreased ERK1/2 activation, and increased tissue inhibitor of metalloproteinase-2 (TIMP-2), and plasminogen activator inhibitor-1 (PAI-1) expression (61). Likewise, in laryngeal squamous cell carcinoma SNU-46 cells, silibinin induced apoptosis (62). Furthermore, silibinin inhibited proliferation, invasion, and angiogenesis in lung carcinoma while simultaneously inducing apoptosis (63–65). Proliferation of Anip973 cells was inhibited by silibinin (66), which in non-small cell lung cancer cell lines corresponded to inhibition of CDK2, CDK4, and Rb phosphorylation, as well as induction of apoptosis by activation of the caspase cascade pathway (63,67). Similar to oral cancer, silibinin treatment concentration- and time-dependently decreased MMP-2 and u-Pa expression through inhibition of either ERK1/2 or Akt phosphorylation along with increasing TIMP-2 expression which together translated to an inhibition of invasiveness in the aggressive human lung adenocarcinoma A549 cells (68,69). Silibinin was reported to decrease expression of COX-2, iNOS, MMP-2, and MMP-9 and inhibit activation of ERK1/2, NF-κB, STAT-1, and STAT-3 in mouse lung epithelial LM2 cells (70). Reduction of iNOS elicited by silibinin treatment was also found in A549 cells (71). In the A/J mouse model of lung cancer, silibinin treatment reduced the number, growth, progression, and angiogenesis of induced tumors which was associated with downregulated VEGF, COX-2, iNOS, HIF-1α, STAT-3, and NF-κB, and increased Ang-2 and Tie-2 (64,65). Furthermore, silibinin enhanced sensitivity of A549 cells to doxorubicin through reduction of NFκ-B-mediated chemoresistance (72). In glioblastoma models, silibinin was shown to inhibit growth and invasiveness and induce apoptosis (73,74). Silibinin was also reported to inhibit EGFR activation in a rat glioma cell line stably expressing human EGFR (75). NF-κB-mediated stimulation of MMP-9 in glioblastoma U87 cells was found to be abrogated by silibinin treatment which served to attenuate invasiveness (74). Silibinin was found to induce caspase-mediated apoptosis by activating MAPKs as well as reverting sensitivity to TRAIL signaling in otherwise resistant glioma cells by modulating components of the death receptor-mediated apoptotic pathway (73,76). Interestingly, in the glioblastoma cell line, U87MG, silibinin appeared to partially synergize with arsenic trioxide treatments to increase apoptosis while inhibiting cell proliferation, metabolism, and mRNA expression of several proteinases (77) suggesting the possibility of combinatorial treatments to arrest cancer. Several studies have also revealed that silibinin offers protection from photo-carcinogenesis in skin cancer models. A key mechanism by which silibinin mitigates UVA- and UVB-induced dysfunction is activation of the DNAPK-p53 pathway, inhibiting DNA synthesis, cellular proliferation, and apoptosis and inducing cell cycle arrest and repair in response to UV-induced DNA damage which together serves to inhibit tumor appearance and growth (78–81). This response is in part mediated by inhibition of ERK1/2, with concomitant increase of p53 and p21/Cip1 (82,83). Furthermore, silibinin was found to abrogate ATP and GSH depletion, ROS production, and lipid peroxidation in UVA-irradiated human keratinocytes, corresponding to inhibition of UVB-induced PARP and caspase 9 cleavage (84,85). These effects operated in conjunction with inhibition of inflammatory mediators such as COX-2, STAT-3, and NF-κB and angiogenic mediators such as HIF-1α and iNOS (86). In MG-63 cells, silibinin treatment reduced osteosarcoma invasiveness which was associated with inhibition of focal adhesion kinase, ERK1/2 activation, and uPA and MMP-2 expression (87). Similarly, in HT1080 cells, silibinin treatment activated p38 and JNK pathways and inhibited ERK and Akt pathways resulting in autophagy (88). In breast cancer models, silibinin induced apoptosis in MCF-7 cells which synergized with inhibition of insulin growth factor receptor (IGFR) (89,90) and also inhibited metastasis of MDA-MB-231 cells (91). In addition, silibinin dose-dependently decreased expression of EGFR ligand-induced CD44, 12-O-tetradecanoylphorbol-13-acetate-induced MMP-9 and VEGF, as well as activation of ERK1/2 (92–94). Interestingly, silibinin induced reactive nitrogen species and ROS generation in MCF-7 cells (95). These phenomena translated to induction of tumor growth arrest and apoptosis in silibinin-treated HER-2/neu transgenic mice (96). In accordance with these findings, silibinin increased apoptosis and induced G2-M cell cycle arrest of A2780/taxol cells, enhancing their sensitivity to paclitaxel, which was associated with the downregulation of survivin and P-glycoproteins (97). In turn, mice xenografts with A2780 cells exhibited a reduction in angiogenic activity in response to silipide (silibinin phytosomes) treatment as a consequence of downregulation of VEGF receptor 3 and upregulation of Ang-2 (98). Together, the abovementioned studies clearly demonstrated the broad spectrum chemopreventive and anticancer efficacy of silibinin. Next, we have focused on silibinin efficacy and mechanism of its action against prostate cancer cells. жүктеу/скачать 2.54 Mb. Достарыңызбен бөлісу:
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