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Zhifei Cao,
Di Yu,
Shilong Fu,
Gaochuan Zhang,
Yanyan Pan,
Meimei Bao,
Jian Tu,
Bingxue Shang,
Pengda Guo,
Ping Yang,
Quansheng Zhou
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ABSTRACT: Uncontrolled tumor cell proliferation and robust neovascularization are prominent features of aggressive ovarian cancers. Although great efforts in anti-ovarian cancer therapy have been made in the past four decades, the 5-year survival rates for ovarian cancer patients are still poor, and effective drugs to cure ovarian cancer patients are absent. In this study, we evaluated the anti-cancer effects of lycorine hydrochloride (LH), a novel anti-ovarian cancer agent, using the highly-invasive ovarian cancer cell line, Hey1B, as a model. Our data showed that LH effectively inhibited mitotic proliferation of Hey1B cells (half maximal inhibitory concentration=1.2μM) with very low toxicity, resulting in cell cycle arrest at the G2/M transition through enhanced expression of the cell cycle inhibitor p21 and marked down-regulation of cyclin D3 expression. Moreover, LH suppressed both the formation of capillary-like tubes by Hey1B cells cultured in vitro and the ovarian cancer cell-dominant neovascularization in vivo when administered to Hey1B-xenotransplanted mice. LH also suppressed the expression of several key angiogenic genes, including VE-cadherin, vascular endothelial growth factor, and Sema4D, and reduced Akt phosphorylation in Hey1B cells. These results suggest that LH selectively inhibits ovarian cancer cell proliferation and neovascularization and is a potential drug candidate for anti-ovarian cancer therapy.
Toxicology Letters 01/2013; · 3.23 Impact Factor
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ABSTRACT: Osteosarcoma is one of the most common malignant bone tumors in children and adolescents. Although extensive efforts have been made in anti-osteosarcoma therapy in recent decades, there are no effective low-toxicity drugs for treating patients with metastatic osteosarcoma. Hence, potent anti-metastatic osteosarcoma drugs are highly desired. In this study, we explored novel small molecular anti-metastatic osteosarcoma agents and found that columbamine, an active component of the herb Coptis Chinensis, inhibited the proliferation and neovascularization of metastatic osteosarcoma U2OS cells. Columbamine effectively suppressed U2OS cell proliferation in vitro with an IC(50) of 21.31±0.38μM, with low cytotoxicity. Mechanistic studies revealed that columbamine induces cell cycle arrest at the G2/M transition, which is associated with attenuating CDK6 gene expression and diminishing STAT3 phosphorylation. Columbamine did not significantly promote U2OS cell apoptosis at any of the dosages tested. Additionally, columbamine inhibited U2OS cell-mediated neovascularization, which was accompanied by the down-regulation of matrix metalloproteinase (MMP) 2 expression and reduction of cell migration, adhesion, and invasion. Taken together, our data show that columbamine exerts anti-proliferative and anti-vasculogenic effects on metastatic human osteosarcoma U2OS cells with low toxicity. These results warrant further investigation of columbamine as a potential anti-osteosarcoma and anti-cancer drug.
Toxicology Letters 11/2012; · 3.23 Impact Factor
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ABSTRACT: Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti-angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti-melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell-dominant formation of capillary-like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE-cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE-cadherin gene in a dose-dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell-dominant vasculogenic mimicry by reducing VE-cadherin gene expression and diminishing cell surface exposure of the protein.
Pigment Cell & Melanoma Research 07/2012; 25(5):630-8. · 5.06 Impact Factor
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ABSTRACT: SZ117 is a monoclonal antibody against matrix metalloproteinase-2 (MMP-2) and exhibits anti-tumor angiogenic effect. In this study, we observed that SZ117 bound to a 280 kDa protein, which was detected in tumor cell-derived Matrigel and various tumor cells. Using immunoprecipitation, mass spectrometry analysis, and Western blot analysis, we identified the 280 kDa protein as filamin A and found that filamin A and its degraded products, notably a 53 kDa fragment, were released from a variety of tumor cells. This suggests that SZ117 is useful in the study of the pathogenesis of filamin A and that blockage of filamin A by SZ117 might contribute to the anti-tumor angiogenic effect of the monoclonal antibody.
Hybridoma (2005) 06/2012; 31(3):214-8. · 0.42 Impact Factor
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ABSTRACT: Anti-lymphoma therapy continues to present a major challenge. Even though cytotoxic therapy, immunotherapy and molecularly targeted therapy have been used in the clinic to treat the disease, effective anti-lymphoma drugs are still needed. In this study, we explored novel anti-lymphoma agents and found that scutellarin, an active component of a traditional Chinese medicinal herb Erigeron breviscapus, executed an anti-lymphoma effect. Scutellarin diminished the proliferation of B-lymphoma Namalwa cells in vitro and inhibited lymphoma growth in Namalwa cell-xenotransplanted mice without obvious toxicity. A mechanism study showed that scutellarin at doses of less than 10 μM induced cell cycle arrest at G0/G1 transition without the induction of cell apoptosis, which was accompanied by down-regulation of cyclin D1 and CDK4 expression. In contrast, scutellarin at concentrations of 15 μM or above promoted Namalwa cell apoptosis, which was partially associated with the activation of caspases. These results suggest that scutellarin is a new potential anti-lymphoma candidate.
Leukemia & lymphoma 05/2012; · 2.40 Impact Factor
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ABSTRACT: Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.
Frontiers of medicine. 03/2012; 6(1):67-78.
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ABSTRACT: Induced pluripotent stem cells (iPSCs) have recently boomed enthusiasm in stem cell therapy, whereas high potential tumorigenesis of iPSCs has become the biggest obstacle for clinic application and the tumorigenic genes in iPSCs have not been well documented. In this investigation, using tools of bioinformatics, we analyzed the all available datasets regarded to iPSCs from 11 differentiated cell lines and revealed 593 iPSC consensus genes. Notably, of the 593 genes, 209 were expressed in human tumor cell lines and cancer tissues, and some of them were expressed in the iPSC-differentiated hepatocytes; remarkably, 5 oncogenes were overexpressed in the iPSCs and an oncogene RAB25 in the iPSC-differentiated cells, suggesting that these iPSC consensus genes are implicated with the risk of tumorigenesis and cancers. This investigation provides useful information for designing new strategies and methods to curtail the expression of oncogenic genes in iPSCs and produce safe iPSC derivatives for stem cell therapy.
Stem cells and development 12/2011; 21(6):955-64. · 4.15 Impact Factor
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ABSTRACT: In this study, using an in vitro tube formation model, we observed that SZ117, a monoclonal antibody against matrix metalloproteinase-2 (MMP2), attenuated a capillary-like tube structure formed by tumor endothelial cell 3B11 and human sarcoma cell MG63. In addition, gelatin zymography showed that SZ117 markedly inhibited MMP2 activity, but did not affect the capability of MMP9-mediated gelatin degradation. These data suggest that SZ117 might have an anti-tumor angiogenic effect and that angiogenic tumor cells and MMP2 may be targeted by monoclonal antibodies for novel anti-tumor angiogenic and anti-cancerous drug discovery.
Hybridoma (2005) 12/2011; 31(1):63-7. · 0.42 Impact Factor
