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Tumor Cell Apoptosis (tumor + cell_apoptosi)
Selected AbstractsLBY135, a novel anti-DR5 agonistic antibody induces tumor cell,specific cytotoxic activity in human colon tumor cell lines and xenografts,DRUG DEVELOPMENT RESEARCH, Issue 2 2008Jing Li Abstract TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis on binding to DR4 and DR5 receptors on the surface of tumor cells. These receptors are of particular interest in the development of cancer therapeutics as they preferentially mediate tumor cell apoptosis. We have generated a chimeric anti-DR5 agonistic antibody, LBY135, from its murine parental antibody, LCR211, identified using hybridoma technology. Both LCR211 and LBY135 specifically bind to DR5 with nanomolar affinity, mimic TRAIL to induce cell death in tumor cells, and have little effect on non-transformed cells in vitro. The anti-DR5 antibody reduced viability in 45% of a panel of 40 human colon cancer cell lines with IC50 values of 20,nM or less. In vivo, using human colorectal tumor xenograft mouse models, LCR211 induced tumor regression and showed enhanced efficacy when combined with 5-FU. Both in vitro evaluation of ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), and in vivo studies using a non-functional DR5 specific antibody or SCID-Beige mice, suggested ADCC and CDC are unlikely to be the mechanism to ablate tumors in vivo. LBY135 and LCR211 appear to mediate cell death and tumor regression mainly through apoptosis, as demonstrated by the activation of caspase 3, caspase 8, M30, and TUNEL assay. In addition, the discovery of synergy between cross-linked LBY135 and TRAIL not only revealed the unique epitope of LBY135, but also demonstrated an additional mechanism of action for LBY135 in vivo. LBY135 demonstrates promise as a novel therapeutic for cancer treatment and is currently in Phase I clinical trials. Drug Dev Res 69: 69,82, 2008. © 2008 Wiley-Liss, Inc. [source] Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing abilityINTERNATIONAL JOURNAL OF CANCER, Issue 2 2010Ying-Yi Li Abstract We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-XL. These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser112 -Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas. [source] Role of the Bone Marrow Microenvironment in Multiple Myeloma,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002G. David Roodman M.D., Ph.D. Abstract On June 26,27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused on the biology of cell-to-cell interactions, the mediators of bone disease, and novel treatment strategies for myeloma. Studies on cell-cell interactions showed that vascular cell adhesion molecule 1, expressed by local endothelial and stromal cells, binds to tumor cell surface integrins in which expression may be increased by tumor cell-derived chemokines such as macrophage inflammatory protein (MIP) 1,. These adhesive interactions increase production and release of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease showed the ligand for receptor activator of nuclear transcription factor-,B (RANKL) was expressed on tumor cells and stromal cells associated with myeloma cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL suppressed osteoclast maturation, bone resorption, and tumor development. Bisphosphonates, in addition to reducing osteoclast mobility and inducing osteoclast apoptosis, also decreased tumor cell adhesion to stroma. Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell-stromal cell interactions, blocking both secretion of cytokines and activation of intracellular signaling pathways required for tumor survival and growth. These agents induced tumor cell apoptosis, decreased neovascularization, and potentiated natural killer cell activity. The proteasome inhibitor PS-341 also prevented expression of adhesion molecules and cytokines and triggered tumor cell apoptosis, even in drug-resistant cell lines, while showing minimal activity in healthy cells. In addition, potential therapeutic agents under investigation, which included RANKL antagonists, protein prenylation inhibitors, and osteoblast growth factors, were discussed. [source] In silico modulation of apoptotic Bcl-2 proteins by mistletoe lectin-1: Functional consequences of protein modificationsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Tasneem A. Khwaja Abstract The mistletoe lectin-1 (ML-1) modulates tumor cell apoptosis by triggering signaling cascades through the complex interplay of phosphorylation and O -linked N -acetylglucosamine (O -GlcNAc) modification in pro- and anti-apoptotic proteins. In particular, ML-1 is predicted to induce dephosphorylation of Bcl-2-family proteins and their alternative O -GlcNAc modification at specific, conserved Ser/Thr residues. The sites for phosphorylation and glycosylation were predicted and analyzed using Netphos 2.0 and YinOYang 1.2. The involvement of modified Ser/Thr, and among them the potential Yin Yang sites that may undergo both types of posttranslational modification, is proposed to mediate apoptosis modulation by ML-1. J. Cell. Biochem. 103: 479,491, 2008. © 2007 Wiley-Liss, Inc. [source] Stromelysin-3 suppresses tumor cell apoptosis in a murine model,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2001Erxi Wu Abstract Stromelysin-3 (STR-3) is a matrix metalloproteinase with a unique pattern of expression and substrate specificity. During embryogenesis and remodeling of normal adult tissues, STR-3 is produced by stromal cells in direct contact with epithelial cells undergoing regional apoptosis and selective cell survival. STR-3 is also overexpressed by interdigitating stromal cells in primary epithelial malignancies. Although STR-3 does not degrade classic extracellular matrix components, the enzyme promotes the establishment of local tumors in nude mice by as yet undefined mechanisms. STR-3 is induced when malignant epithelial cells come into contact with surrounding stromal elements; the active stromal cell-derived 45 kDa enzyme is subsequently processed to a 35 kDa protein without enzymatic activity. We have generated MCF-7 transfectants expressing wild type or catalytically inactive 45 kDa STR-3 (STR-3wt and STR-3cat- ) or secreted 35 kDa STR-3 (35 kDa STR-3sec) and evaluated their implantation and survival in nude mice. Tumors developed significantly more rapidly in animals receiving STR-3wt, rather than vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Most importantly, STR-3wt tumors had a significantly lower percentage of apoptotic cells than tumors derived from vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Taken together, these studies suggest that the active STR-3 enzyme may increase tumor take by suppressing tumor cell apoptosis and that 45 kDa to 35 kDa STR-3 processing limits STR-3 activity at the tumor/stromal interface. Because STR-3 is secreted as an active enzyme rather than a proform, subsequent 45 kDa to 35 kDa STR-3 processing may represent a novel mechanism for regulating enzymatic activity. J. Cell. Biochem. 82: 549,555, 2001. © 2001 Wiley-Liss, Inc. [source] Studies on search for bioactive natural products targeting TRAIL signaling leading to tumor cell apoptosisMEDICINAL RESEARCH REVIEWS, Issue 5 2008Masami Ishibashi Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells and, hence, has been expected as a new anticancer strategy. During our studies on search for bioactive natural products from various natural resources such as plants and microorganisms, we recently identified several natural products which exhibited activities related to TRAIL signaling. Dimeric sesquiterpenoids isolated from Zingiberaceous plant, Curcuma parviflora, showed enhancement activity of gene expression of TRAIL-receptor and TRAIL-receptor protein level. Several new isoflavone natural products, named brandisianins, were isolated from Leguminosaeous plant, Millettia brandisiana, by our screening study targeting TRAIL-receptor expression enhancement activity. A dihydroflavonol (BB1) that was extracted from Compositaeous plant, Blumea balsamifera, and fuligocandin B, a new anthranilylproline-indole alkaloid isolated from myxomycete were found to exhibit reversal effect of TRAIL resistance activity. © 2008 Wiley Periodicals, Inc. Med Res Rev, 28, No. 5, 688,714, 2008 [source] Neem leaf preparation induces apoptosis of tumor cells by releasing cytotoxic cytokines from human peripheral blood mononuclear cellsPHYTOTHERAPY RESEARCH, Issue 10 2007Anamika Bose Abstract A neem leaf preparation (NLP) was investigated for its role in the induction of tumor cell apoptosis to elucidate the mechanism of NLP mediated immunoprophylaxis in tumor growth restriction. As NLP did not induce direct apoptosis of human tumor cell lines KB, MCF7 and K562, it was used instead to stimulate human peripheral blood mononuclear cells (PBMC) for 72 h. The PBMC derived culture supernatant (NLP-CS) was observed to induce the restriction of tumor cell proliferation as well as apoptosis. An enzyme linked immunosorbant assay revealed the presence of cytotoxic cytokines, IFN-gamma and TNF-alpha, in the NLP-CS. The inhibition of secretion of IFN-gamma and TNF-alpha in NLP-CS caused a significant decrease in tumor cell apoptosis. Furthermore, stimulation of these tumor cells with NLP-CS resulted in upregulation of the caspase 3 and downregulation of the Bcl 2 and cyclin D1. These observations suggested that NLP could induce tumor cellular apoptosis by releasing cytotoxic cytokines from human PBMC. Copyright © 2007 John Wiley & Sons, Ltd. [source] A retrovirus-based system to stably silence GDF-8 expression and enhance myogenic differentiation in human rhabdomyosarcoma cellsTHE JOURNAL OF GENE MEDICINE, Issue 8 2008Zhuo Yang Abstract Background Myostatin, also called GDF-8, a secreted growth and differentiating factor that belongs to the transforming growth factor-, superfamily, is a known negative regulator of myogenesis in vivo. Overexpression of GDF-8 contributes to the lack of differentiation in human rhabdomyosarcoma (RMS) cells. We investigated whether a retrovirus-based RNA interference (RNAi) system against GDF-8 expression in human RMS cells would enhance myogenic differentiation. Methods A retrovirus-based RNAi system was developed that utilized the U6-RNA polymerase III promoter to drive efficient expression and deliver the GDF8-specific short hairpin RNAs (shRNAs) in human RMS cell A204. In this system, the retrovirus vector was integrated into the host cell genome and allowed stable expression of shRNAs. GDF-8 expression was determined by real-time polymerase chain reaction and western blotting analysis. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the cell proliferation. Myogenic differentiation markers were monitored by western blotting analysis. Cell cycle and apoptosis was determined by propidium iodide staining and analysed in a flow cytometer. Results In the siGDF8 A204 cell pools, the levels of both GDF-8 mRNA and protein were dramatically reduced by this RNAi system. In differentiation conditions, inhibition of myostatin synthesis led to enhanced cell cycle withdrawal, consequently stimulated myogenic differentiation and increased the rate of tumor cell apoptosis. Conclusions The results demonstrate that deactivation of myostatin by using retrovirus-based RNAi thus may be useful for therapy in rhabdomyosarcomas. Copyright © 2008 John Wiley & Sons, Ltd. [source] Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasisTHE JOURNAL OF GENE MEDICINE, Issue 4 2005Zhuang Chen Abstract Background Tumor metastasis and relapse are major obstacles in combating human malignant diseases. Neither radiotherapy alone nor injection of dendritic cells (DCs) can successfully overcome this problem. Radiation induces tumor cell apoptosis and necrosis, resulting in the release of tumor antigen and danger signals, which are favorable for DC capturing antigens and maturation. Hence, the strategy of combined irradiation and DC vaccine may be a novel approach for treating human malignancies and early metastasis. Methods To develop an effective combined therapeutic approach, we established a novel concomitant local tumor and liver metastases model through subcutaneous (s.c.) and intravenous (i.v.) injection. We selected the optimal time for DC injection after irradiation and investigated the antitumor effect of combining irradiation with DC intratumoral injection and the related mechanism. Results Combined treatment with radiotherapy and DC vaccine could induce a potent antitumor immune response, resulting in a significant decrease in the rate of local tumor relapse and the numbers of liver metastases. The related mechanisms for this strong antitumor immunity of this combined therapy might be associated with the production of apoptotic and necrotic tumor antigens and heat shock proteins after irradiation, phagocytosis, migration and maturation of DCs, and induction of more efficient tumor-specific cytotoxic T lymphocyte activity through a cross-presentation pathway. Conclusions Co-administration of local irradiation and intratumoral DC injection may be a promising strategy for treating radiosensitive tumors and eliminating metastasis in the clinic. Copyright © 2004 John Wiley & Sons, Ltd. [source] Killing tumor cells through their surface ,2 -microglobulin or major histocompatibility complex class I moleculesCANCER, Issue 7 2010Jing Yang PhD Abstract Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for ,2 -microglobulin (,2M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against ,2M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-,2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although ,2M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting ,2M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for ,2M/MHC class I-expressing malignancies. Cancer 2010. © 2010 American Cancer Society. [source] | ||||||||||||||||||||||