Расторопши: семена ранней потенциальных
Details of broad-spectrum anti-metastatic efficacy of silibinin
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- Breast cancer
- Lung Cancer
- Osteosarcoma
- Oral Cancer
Details of broad-spectrum anti-metastatic efficacy of silibininThere are numerous studies suggesting the broad-spectrum efficacy of silibinin in inhibiting cancer metastasis. These studies are elaborated in detail below: Prostate cancerWe first reported the anti-metastatic potential of silibinin in TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice, which is a most-frequently utilized pre-clinical model to evaluate the in vivo efficacy of cancer chemopreventive and therapeutic agents against prostate cancer. In this model, mice develop spontaneous progressive stages of prostate cancer that is driven by the expression of SV40 early genes (T/t; Tag) specifically in the prostatic epithelium. In these mice, all stages of human prostate cancer are recapitulated from early lesions of prostate intraepithelial neoplasia (PIN) to late stage metastatic adenocarcinoma. We reported that silibinin feeding (as siliphos) for 11 weeks (20–31 weeks of TRAMP male mice age) strongly inhibits the progression of PIN into the advanced stages of prostate cancer [90]. Importantly, in this study, silibinin feeding strongly inhibited the local invasion of prostate cancer cells to seminal vesicle [90]. Further, a phenomenal anti-metastatic effect of silibinin was reported with no secondary tumors in distant organs (liver and kidney) in silibinin-fed mice [90]. The strong anti-metastatic efficacy of silibinin in TRAMP mice model was also evident where silibinin was fed in a stage specific manner [80]. This study showed that TRAMP mice develop distant metastasis between 12–20 week age and number of metastatic lesion increases with the increasing age of the mice [80]. However, in this study, silibinin feeding during 12–20 weeks (age of TRAMP mice) significantly inhibited the lung metastasis; it also strongly decreased the metastasis to liver, lung and kidney when fed between 20–30 and 30–45 weeks of TRAMP mice age [80]. These two studies clearly established the strong anti-metastatic efficacy of silibinin in prostate cancer cells in vivo. Anti-migratory and anti-invasive efficacy of silibinin has also been reported in numerous cell culture studies [91–94]. Mokhtari et al. reported that silibinin treatment strongly inhibits migratory potential of human prostate carcinoma PC3 cells [91]. In another study, Wu et al. reported the dose-and time-dependent inhibitory effects of silibinin on the migratory and invasive characteristics of highly bone metastatic ARCaP(M) cells [93]. We have also observed similar strong inhibitory effect of silibinin on the migratory and invasive potential of three human prostate cancer cell lines namely PC3, PC3MM2 and C4-2B cells in wound healing and invasion chamber assays, respectively [94]. Importantly, in these studies the anti-invasive and anti-migratory effect of silibinin was evident at concentrations where its cytotoxicity to cancer cells was minimal [91,93,94]. Cell-matrix interaction replaces cell-cell interaction during EMT in cancer cells, and plays important role in the growth, motility and invasiveness of cancer cells [14,15]. Silibinin treatment has been reported to significantly decrease the adhesion of PC3 cells with type I collagen [91]. It is important to mention here that bones are rich in type I collagen, therefore, interaction of prostate cancer cells with type I collagen is also important at distant metastatic bone site. Silibinin treatment also inhibited the adhesion of human prostate cancer PC3M cells with ECM proteins hyaluronan and fibronectin through targeting the expression of transmembrane protein CD44 and its variant form CD44v7-10 [95]. These studies suggest that silibinin treatment significantly attenuates the interaction of prostate cancer cells with their ECM components, which could adversely affect their motility and invasiveness. As mentioned earlier, prostate cancer cells have high propensity to metastasize to bones [3]. During bone metastasis, prostate cancer cells even express genes like osteocalcin, bone sialoprotein, osteopontin, RANK ligand (RANKL), whose expression is normally restricted to bone cells [13,96]. This phenomenon is termed as ‘osteomimicry’ and is considered as an extreme effort by prostate cancer cells to adapt to their microenvironment. Our unpublished data has shown that silibinin could target many osteomimicry related proteins such as RANKL in prostate cancer cells. Once settled in bones, prostate cancer cells alter the delicate balance of bone remodeling orchestrated by two types of bone cells namely osetoclasts (involved in bone degradation) and osteoblasts (involved in bone formation) [12,13,96]. Prostate cancer cells secrete factors like RANKL, PTHrP (parathyroid hormone-related peptide) and uPA (urokinase-type plasminogen activator) that are involved in osetoclasts maturation and activation; thereby promote bone mineralization and liberation of various growth factors including TGF-β, IGFs, BMPs, PDGF etc [12,13,96]. Bone degradation provides prostate cancer cells the initial space to expand, and the released growth factors promote prostate cancer cell survival and proliferation. These growth factors secreted by bone degradation and those secreted by prostate cancer cells like endothelin-1 (ET-1), BMPs, Wnts, promote osteoblasts maturation and formation of new bone [12,13,96]. Mature osteoblasts also secrete growth factors which further promote prostate cancer cells growth in bone [13,96]. Overall, this vicious cycle involving prostate cancer cells, osteoclasts and osteoblasts promotes bone degradation as well as deposition of new ‘woven type bone’ (uneven/immature/embryonic), and thereby compromises bone health and leads to bone complications in prostate cancer patients. Since the initiation of osteoclastogenesis is the critical step in the establishment of prostate cancer growth in bone; targeting osteoclastogenesis has been considered a novel strategy against the bone metastasis by prostate cancer cells. Importantly, silibinin has been reported to significantly target osteoclastogenesis [97,98]. Kim et al. reported that silibinin treatment strongly inhibits RANKL-induced osteoclastogenesis in pre-osteoclastic RAW264.7 cells and in bone marrow-derived monocyte/macrophage cells [97]. This study also showed that silibinin significantly decreases TNF-α-induced osteoclastogenesis in osteoclast precursor cells from bone marrow [97]. Silibinin treatment also inhibited the osteoclastogenesis in bone marrow cells incubated directly with osteoblasts in the presence of 1,25(OH)2D3 [97]. In our ongoing studies, we observed that the exposure of RAW264.7 cells to the conditioned media from prostate cancer cells increases their osteoclastic activity as well as number of differentiated osteoclasts [98]. However, conditioned media collected from silibinin pre-treated prostate cancer cells (PC3, PC3MM2 and C4-2B) has significantly lesser potency to induce osteoclastic activity or osteoclastic differentiation in RAW264.7 cells [98]. These studies clearly suggest that silibinin treatment could alter the tumor microenvironment towards lowering the metastatic growth of prostate cancer cells. Breast cancerBreast cancer is one of the leading causes of cancer-related incidences and mortality among women [1]. In most breast cancer cases, death occurs due to metastatic spread of cancer cells to distant organs mainly to bone, liver, lung and brain. Provinciali et al. first studied the effect of silibinin treatment (in the form of silipide) on the development of mammary tumors in HER-2/neu transgenic mice [99]. In these mice, the overexpression of HER-2/neu is under the control of the mouse mammary tumor virus promoter, and these mice spontaneously develop tumors in their mammary glands at an early age. This study showed that silibinin treatment delays the development of spontaneous mammary tumors and reduces the number of mammary tumor masses [99]. Importantly, in this study, silibinin treatment significantly reduced the percentage of mice with lung metastasis as well as the mean size of lung metastasis [99]. This anti-cancer efficacy of silibinin was mainly attributed to the down-regulation of HER-2/neu expression, and the induction of senescent-like growth arrest and apoptosis through a p53-mediated pathway [99]. In another in vitro study, Lee et al. reported that silibinin treatment significantly inhibits the PMA (phorbol 12-myristate)-induced invasiveness of MCF-7 human breast carcinoma cells [100]. These in vivo and in vitro studies suggest that silibinin could effectively inhibit metastasis of breast cancer cells. Lung CancerLung cancer is the most common cause of death due to cancer in both men and women around the world. Lung cancer cells tend to metastasize very early after their primary growth, and that is one of the reasons that lung cancer is a very life-threatening cancer and one of the most difficult cancers to treat. While lung cancer can spread to any organ in the body, certain organs like adrenal glands, liver, brain and bone are the most common sites for lung cancer metastasis. Chen et al. analyzed the effect of silibinin feeding on the metastatic potential of Lewis lung carcinoma cells injected sub-cutaneously in C57BL/6 male mice [101]. This study showed that silibinin treatment significantly decreases the tumor mass, tumor volume as well as lung metastases [101]. In another study, Chu et al. showed that silibinin treatment exerts a dose- and time-dependent inhibitory effect on the migratory and invasive potential of human lung cancer A549 cells [102]. These studies suggest that silibinin could effectively target the invasive and metastatic potential of lung cancer cell. OsteosarcomaOsteosarcoma is the most common primary malignant tumor of the bone, and 80% of osteosarcoma patients develop pulmonary and hepatic metastases. Hsieh et al. showed that silibinin treatment significantly decreases the migratory and invasive potential of osteosarcoma MG-63 cells [103]. Silibinin treatment also inhibited the adhesive capability of MG-63 cells towards type IV collagen [103]. Further studies are awaited to confirm the in vivo anti-metastatic efficacy of silibinin against osteosarcoma cells. Oral CancerSquamous cell carcinoma of the tongue is a common malignancy of the oral cavity and these cancer cells usually metastasize to lymph nodes of the neck. Study by Chen et al. showed the inhibitory effect of silibinin on the migratory and invasive potential of human tongue squamous cell carcinoma cells in vitro [101]. Silibinin treatment also affected the interaction of these cancer cells with type I collagen [101]. These in vitro studies still need to be confirmed in in vivo model of oral cancer metastasis. жүктеу/скачать 2.54 Mb. Достарыңызбен бөлісу:
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