scholarly journals The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5516
Author(s):  
Lawrence David Mason ◽  
Suresh Chava ◽  
Kiran Kumar Reddi ◽  
Romi Gupta
Keyword(s):  
Extracellular Matrix ◽  
Tumor Growth ◽  
Resistance Mechanisms ◽  
Therapeutic Agents ◽  
Oncogenic Signaling ◽  
Melanoma Tumor ◽  
Term Survival ◽  
Ecm Proteins ◽  
Melanoma Patients ◽  
Melanoma Growth

Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.

Effect of mebendazole on melanoma xenograft growth through targeting of bcl-2

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9075-9075
Author(s):  
N. A. Doudican ◽  
R. Pennell ◽  
T. Tu ◽  
L. Liebes ◽  
A. Pavlick ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Melanoma Cells ◽  
High Dose ◽  
Tumor Diameter ◽  
Proliferating Cells ◽  
Melanoma Tumor ◽  
Mouse Xenograft Model ◽  
Melanoma Growth

9075 Background: Defects in apoptosis are thought to contribute to melanoma chemoresistance, making the anti-apoptotic protein Bcl-2 an attractive therapeutic target. We identified mebendazole (MBZ), a microtubule binding agent, as an inducer of melanoma cytotoxicity via a Bcl-2 dependent mechanism in vitro (Mol Cancer Res, Aug 2008). In the present study, we assessed the effect of MBZ on human melanoma tumor growth and progression in a mouse xenograft model and compared the ability of MBZ to inhibit growth of cultured melanoma cells to that of oblimersen (OBL), an antisense drug targeting Bcl-2. Methods: Growth of human M-14 melanoma xenografts in mice administered MBZ orally at doses from 0.1 to 2 mg were compared to tumor growth in mice receiving 100mg/kg intraperitoneal temozolomide (TMZ) or vehicle alone. Tumor diameter, volume, histopathology, and immunohistochemical staining of caspase 3 and Ki67 were assessed. Bcl-2 phosphorylation was determined by immunoblotting. MBZ and OBL-induced melanoma growth inhibition was analyzed by MTT assay. Results: Anti-melanoma effects of MBZ were dose- dependent up to 1 mg which displayed a 72% reduction in tumor volume compared to vehicle treated mice. This reduction in volume was accompanied by a 46% decrease in proliferating cells and an 81% increase in apoptotic cells. Moreover, 1 mg MBZ inhibited tumor growth as effectively as high dose TMZ, the current melanoma standard of care. Orally administered MBZ treatment resulted in Bcl-2 phosphorylation in vivo, further confirming its mechanism of action. MBZ inhibited growth of melanoma cells in culture more effectively than OBL with GI50 values of 0.32 uM and 7.45 uM, respectively. Conclusions: MBZ safely and effectively inhibits melanoma growth and progression in a xenograft model. A phase II clinical trial investigating MBZ's utility as adjuvant therapy in patients with stage IV, resected melanoma is planned. No significant financial relationships to disclose.

Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3361-3368 ◽  
Author(s):  
William W. Spurbeck ◽  
Catherine Y. C. Ng ◽  
Ted S. Strom ◽  
Elio F. Vanin ◽  
Andrew M. Davidoff
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Matrix Metalloproteinases ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Severe Combined Immunodeficiency ◽  
Melanoma Tumor ◽  
Vitro Assay ◽  
Capillary Morphogenesis

Abstract Homeostasis of the extracellular matrix is a delicate balance between degradation and remodeling, the balance being maintained by the interaction of activated matrix metalloproteinases (MMPs) and specific tissue inhibitors of matrix metalloproteinases (TIMPs). Up-regulation of MMP activity, favoring proteolytic degradation of the basement membrane and extracellular matrix, has been linked to tumor growth and metastasis, as well as tumor-associated angiogenesis, whereas inhibition of MMP activity appears to restrict these processes. We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit angiogenesis in vivo. Growth of both histologic types of gene-modified tumor cells in severe combined immunodeficiency (SCID) mice was significantly restricted when compared with controls. Grossly, these tumors were small and had few feeding vessels. Histologic evaluation revealed that although tumors overexpressing TIMP-3 had an increased number of CD31+endothelial cells, these endothelial cells had not formed functional tubules, as evidenced by decreased vessel continuity and minimal pericyte recruitment. This effect appears to be mediated, in part, by decreased expression of vascular endothelial (VE)–cadherin by endothelial cells in the presence of TIMP-3 as seen both in an in vitro assay and in TIMP-3–overexpressing tumors. Taken together, these results demonstrate that overexpression of TIMP-3 can inhibit angiogenesis and associated tumor growth, and that the antiangiogenic effects of TIMP-3 appear to be mediated through the inhibition of functional capillary morphogenesis.

scholarly journals Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1984
Author(s):  
Elke Pach ◽  
Jürgen Brinckmann ◽  
Matthias Rübsam ◽  
Maike Kümper ◽  
Cornelia Mauch ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ex Vivo ◽  
Dermal Fibroblasts ◽  
Negative Regulator ◽  
Type I ◽  
Melanoma Tumor ◽  
Stromal Fibroblasts ◽  
Melanoma Growth

Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14Sf−/−) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14Sf−/− mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14Sf−/− skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced melanoma tumor growth. In summary, we show that MMP14 expression in stromal fibroblasts regulates melanoma tumor progression by modifying the peritumoral matrix and point to collagen accumulation as a negative regulator of melanoma.

Cationic Antimicrobial Peptides for Tuberculosis: A Mini-Review

2019 ◽  
Vol 20 (9) ◽  
pp. 885-892
Author(s):  
Sara Silva ◽  
Nuno Vale
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Amino Acid ◽  
Antimicrobial Peptides ◽  
Resistance Mechanisms ◽  
Therapeutic Agents ◽  
Pharmacological Properties ◽  
Therapeutic Activity ◽  
Alternative Strategies ◽  
Cationic Antimicrobial Peptides ◽  
Specific Amino Acid

Cationic antimicrobial peptides (CAMPs) can be considered as new potential therapeutic agents for Tuberculosis treatment with a specific amino acid sequence. New studies can be developed in the future to improve the pharmacological properties of CAMPs and also understand possible resistance mechanisms. This review discusses the principal properties of natural and/or synthetic CAMPs, and how these new peptides have a significant specificity for Mycobacterium tuberculosis. Also, we propose some alternative strategies to enhance the therapeutic activity of these CAMPs that include coadministration with nanoparticles and/or classic drugs.

Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth

2017 ◽  
Vol 385 ◽  
pp. 243-250 ◽  
Author(s):  
Raghavendra Gowda ◽  
Arati Sharma ◽  
Gavin P. Robertson
Keyword(s):  
Tumor Growth ◽  
Inhibitory Effects ◽  
Melanoma Tumor

scholarly journals Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo

2005 ◽  
Vol 201 (3) ◽  
pp. 385-396 ◽  
Author(s):  
Stefan Kraft ◽  
Tony Fleming ◽  
James M. Billingsley ◽  
Shih-Yao Lin ◽  
Marie-Hélène Jouvin ◽  
...  
Keyword(s):  
Pi3k Pathway ◽  
Therapeutic Agents ◽  
Allergic Reactions ◽  
Ecm Proteins ◽  
Broad Array ◽  
High Affinity Ige Receptor ◽  
Nonadherent Cells ◽  
Tetraspanin Cd63

High-affinity IgE receptor (FcεRI) cross-linking on mast cells (MCs) induces secretion of preformed allergy mediators (degranulation) and synthesis of lipid mediators and cytokines. Degranulation produces many symptoms of immediate-type allergic reactions and is modulated by adhesion to surfaces coated with specific extracellular matrix (ECM) proteins. The signals involved in this modulation are mostly unknown and their contribution to allergic reactions in vivo is unclear. Here we report the generation of monoclonal antibodies that potently suppress FcεRI-induced degranulation, but not leukotriene synthesis. We identified the antibody target as the tetraspanin CD63. Tetraspanins are membrane molecules that form multimolecular complexes with a broad array of molecules including ECM protein-binding β integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits FcεRI-mediated degranulation in cells adherent to those ECM proteins but not in nonadherent cells. Thus the inhibition of degranulation by anti-CD63 correlates with its effect on adhesion. In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcεRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2–PI3K pathway that is known to be essential for both degranulation and adhesion. Finally, we showed that these antibodies inhibited FcεRI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases.

Long-Term Survival of a Patient with Hepatocellular Carcinoma under Treatment with Viscum album – Case Report

2021 ◽  
pp. 237-243
Author(s):  
Ana Catarina Viana Valle ◽  
Aloísio Cunha de Carvalho
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Liver Neoplasm ◽  
Viscum Album ◽  
Health Condition ◽  
Continuous Treatment ◽  
Term Survival ◽  
History Of ◽  
Application Frequency

Hepatocellular carcinoma (HCC) is the most common liver neoplasm in dogs and can be treated by the Viscum album therapy in a curative or palliative way. The objective is to report a hepatocellular carcinoma case in a dog treated by homeopathic therapy, extending to Palliative Care, with a 24-month survival. A 12-year-old Schnauzer male with a history of a liver nodule was treated by intravenous and subcutaneous applications of V. album in different dynamization and combinations, chromotherapy, and oral homeopathic medicines. The tumor growth was controlled, and the health condition of the patient was stable while the medication was given as prescribed. However, as application frequency was reduced, tumor growth increased, and health deterioration was verified. Nevertheless and contrary to expectations, the patient had a 24-month survival. Therefore, these findings point to the potential of V. album on enhancing the quality of life, controlling tumor growth, and prolonging survival on patients with HCC. Patients under continuous treatment would benefit better of these properties.

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