|
1
|
Cai Z, Li W, Wang H, Yan W, Zhou Y, Wang G, Cui J, Wang F. Anti-tumor and immunomodulating activities of a polysaccharide from the root of Sanguisorba officinalis L. Int J Biol Macromol 2012; 51:484-8. [DOI: 10.1016/j.ijbiomac.2012.05.029] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 05/18/2012] [Accepted: 05/24/2012] [Indexed: 12/31/2022]
|
|
2
|
Miller RE, Roudier M, Jones J, Armstrong A, Canon J, Dougall WC. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther 2008; 7:2160-9. [PMID: 18606716 DOI: 10.1158/1535-7163.mct-08-0046] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tumor cells induce excessive osteoclastogenesis, mediating pathologic bone resorption and subsequent release of growth factors and calcium from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. RANK ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. In metastatic prostate cancer models, RANKL inhibition directly prevents osteolysis via blockade of osteoclastogenesis and indirectly reduces progression of skeletal tumor burden by reducing local growth factor and calcium concentrations. Docetaxel, a well-established chemotherapy for metastatic hormone-refractory prostate cancer, arrests the cell cycle and induces apoptosis of tumor cells. Suppression of osteoclastogenesis through RANKL inhibition may enhance the effects of docetaxel on skeletal tumors. We evaluated the combination of the RANKL inhibitor osteoprotegerin-Fc (OPG-Fc) with docetaxel in a murine model of prostate cancer bone metastasis. Tumor progression, tumor area, and tumor proliferation and apoptosis were assessed. OPG-Fc alone reduced bone resorption (P < 0.001 versus PBS), inhibited progression of established osteolytic lesions, and reduced tumor area (P < 0.0001 versus PBS). Docetaxel alone reduced tumor burden (P < 0.0001 versus PBS) and delayed the development of osteolytic lesions. OPG-Fc in combination with docetaxel suppressed skeletal tumor burden (P = 0.0005) and increased median survival time by 16.7% (P = 0.0385) compared with docetaxel alone. RANKL inhibition may enhance docetaxel effects by increasing tumor cell apoptosis as evident by increased active caspase-3. These studies show that inhibition of RANKL provides an additive benefit to docetaxel treatment in a murine model of prostate cancer bone metastasis and supports clinical evaluation of this treatment option in patients.
Collapse
Affiliation(s)
- Robert E Miller
- Department of Hematology/Oncology Research, Amgen Washington, Seattle, Washington 98119-3105, USA
| | | | | | | | | | | |
Collapse
|
|
3
|
Choedon T, Mathan G, Arya S, Kumar VL, Kumar V. Anticancer and cytotoxic properties of the latex of Calotropis procera in a transgenic mouse model of hepatocellular carcinoma. World J Gastroenterol 2006; 12:2517-22. [PMID: 16688796 PMCID: PMC4087983 DOI: 10.3748/wjg.v12.i16.2517] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the anticancer property of the dried latex (DL) of Calotropis procera, a tropical medicinal plant, in the X15-myc transgenic mouse model of hepatocellular carcinoma and to elucidate its mechanism of action in cell culture.
METHODS: The young transgenic mice were orally fed with the aqueous suspension of DL (400 mg/kg for 5 d/wk) for 15 wk and their liver was examined for histopathological changes at 20 wk. Serum levels of vascular endothelial growth factor (VEGF) were also measured in these animals. To characterize the active fraction, DL was extracted with petroleum ether followed by methanol. The methanolic extract was sub-fractionated on a silica gel G column using a combination of non-polar and polar solvents and eleven fractions were obtained. Each fraction was analysed for cytotoxic effect on hepatoma (Huh7) and non-hepatoma (COS-1) cell lines and non-transformed hepatocytes (AML12) using tetrazolium (MTT) assay. Finally, the mechanism of cell death was investigated by measuring the levels of Bcl2, caspase 3 and DNA fragmentation.
RESULTS: DL treatment of mice showed a complete protection against hepatocarcinogenesis. No adverse effect was observed in these animals. The serum VEGF level was significantly lowered in the treated mice as compared to control animals. Cell culture studies revealed that the methanolic extract of DL as well as its fraction 8 induced extensive cell death in both Huh-7 and COS-1 cells while AML12 cells were spared. This was accompanied by extensive fragmentation of DNA in Huh-7 and COS-1 cells. No change in the levels of canonical markers of apoptosis such as Bcl2 and caspase 3 was observed.
CONCLUSION: DL of C. procera has the potential for anti-cancer therapy due to its differentiable targets and non-interference with regular pathway of apoptosis.
Collapse
Affiliation(s)
- Tenzin Choedon
- International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India
| | | | | | | | | |
Collapse
|
|
4
|
Ifon ET, Pang ALY, Johnson W, Cashman K, Zimmerman S, Muralidhar S, Chan WY, Casey J, Rosenthal LJ. U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3. Cancer Cell Int 2005; 5:19. [PMID: 15972109 PMCID: PMC1200560 DOI: 10.1186/1475-2867-5-19] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2004] [Accepted: 06/22/2005] [Indexed: 12/12/2022] Open
Abstract
Background Insensitivity of advanced-stage prostate cancer to androgen ablation therapy is a serious problem in clinical practice because it is associated with aggressive progression and poor prognosis. Targeted therapeutic drug discovery efforts are thwarted by lack of adequate knowledge of gene(s) associated with prostate tumorigenesis. Therefore there is the need for studies to provide leads to targeted intervention measures. Here we propose that stable expression of U94, a tumor suppressor gene encoded by human herpesvirus 6A (HHV-6A), could alter gene expression and thereby inhibit the tumorigenicity of PC3 cell line. Microarray gene expression profiling on U94 recombinant PC3 cell line could reveal genes that would elucidate prostate cancer biology, and hopefully identify potential therapeutic targets. Results We have shown that stable expression of U94 gene in PC3 cell line inhibited its focus formation in culture, and tumorigenesis in nude mice. Moreover gene expression profiling revealed dramatic upregulation of FN 1 (fibronectin, 91 ± 16-fold), and profound downregulation of ANGPTL 4 (angiopoietin-like-4, 20 ± 4-fold) in U94 recombinant PC3 cell line. Quantitative real-time polymerase chain reaction (QRT-PCR) analysis showed that the pattern of expression of FN 1 and ANGPTL 4 mRNA were consistent with the microarray data. Based on previous reports, the findings in this study implicate upregulation of FN 1 and downregulation of ANGPTL 4 in the anti tumor activity of U94. Genes with cancer inhibitory activities that were also upregulated include SERPINE 2 (serine/cysteine protease inhibitor 2, 7 ± 1-fold increase) and ADAMTS 1 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7 ± 2-fold increase). Additionally, SPUVE 23 (serine protease 23) that is pro-tumorigenic was significantly downregulated (10 ± 1-fold). Conclusion The dramatic upregulation of FN 1 and downregulation of ANGPTL 4 genes in PC3 cell line stably expressing U94 implicate up-regulation of FN 1 and downregulation of ANGPTL 4 in anti tumor activity of U94. Further studies are necessary to determine functional roles of differentially expressed genes in U94 recombinant PC3 cell line, and hopefully provide leads to potential therapeutic targets in prostate cancer.
Collapse
Affiliation(s)
- Ekwere T Ifon
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - Alan LY Pang
- Laboratory of Clinical Genomics, NICHD, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Warren Johnson
- Laboratory of Clinical Genomics, NICHD, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Kathleen Cashman
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - Sharon Zimmerman
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - Sumitra Muralidhar
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - Wai-Yee Chan
- Laboratory of Clinical Genomics, NICHD, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Department of Pediatrics, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, D.C. 20057, USA
- Department of Cell Biology, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, D.C. 20057
- Department of Biochemistry & Molecular Biology, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - John Casey
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| | - Leonard Jason Rosenthal
- Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20057, USA
| |
Collapse
|
|
5
|
Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola TC, Begtrup JL, Peterson TE, Fingleton B, Shirai T, Matrisian LM, Futakuchi M. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 2005; 7:485-96. [PMID: 15894268 DOI: 10.1016/j.ccr.2005.04.013] [Citation(s) in RCA: 252] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2004] [Revised: 02/28/2005] [Accepted: 04/05/2005] [Indexed: 01/07/2023]
Abstract
We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the tumor-bone interface, was capable of processing RANKL to a soluble form that promoted osteoclast activation. MMP-7-deficient mice demonstrated reduced prostate tumor-induced osteolysis and RANKL processing. This study suggests that inhibition of MMP-7 will have therapeutic benefit in the treatment of prostate cancer-induced osteolysis.
Collapse
Affiliation(s)
- Conor C Lynch
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Stewart DA, Cooper CR, Sikes RA. Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer. Reprod Biol Endocrinol 2004; 2:2. [PMID: 14711377 PMCID: PMC320496 DOI: 10.1186/1477-7827-2-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2003] [Accepted: 01/07/2004] [Indexed: 01/02/2023] Open
Abstract
Prostate cancer (PCa) is no exception to the multi-step process of metastasis. As PCa progresses, changes occur within the microenvironments of both the malignant cells and their targeted site of metastasis, enabling the necessary responses that result in successful translocation. The majority of patients with progressing prostate cancers develop skeletal metastases. Despite advancing efforts in early detection and management, there remains no effective, long-term cure for metastatic PCa. Therefore, the elucidation of the mechanism of PCa metastasis and preferential establishment of lesions in bone is an intensive area of investigation that promises to generate new targets for therapeutic intervention. This review will survey what is currently know concerning PCa interaction with the extracellular matrix (ECM) and the roles of factors within the tumor and ECM microenvironments that contribute to metastasis. These will be discussed within the context of changes in expression and functional heterodimerization patterns of integrins, changes in ECM expression and reorganization by proteases facilitating invasion. In this context we also provide a brief summary of how growth factors (GFs), cytokines and regulatory signaling pathways favor PCa metastasis to bone.
Collapse
Affiliation(s)
- Delisha A Stewart
- Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Carlton R Cooper
- Cancer Biology Laboratory, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Robert A Sikes
- Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| |
Collapse
|