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Anti-VEGF Mediated Immunomodulatory Role of Phytochemicals: Scientific Exposition for Plausible HCC Treatment.
Kumar, AR, Devan, AR, Nair, B, Nath, LR
Current drug targets. 2021;(11):1288-1316
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid tumours and the second leading cause of cancer-related mortality worldwide. Advanced-recurrent HCC often requires a systemic drug therapy where multi tyrosine kinase inhibitor, Sorafenib represents the first-line therapy option. But it exhibited very limited survival benefit and tumour response due to the early emergence of drug resistance and drug-related adverse effect. Immunotherapy approaches now being widely studied as an effective alternative treatment for HCC. Several immune checkpoint inhibitors (ICI), such as Nivolumab and Pembrolizumab, are approved as monotherapy in sorafenib-resistant HCC patients. But, the existence of a plethora of immunosuppressive signals in the tumour microenvironment often leads to unsuccessful immunotherapies. In this context, combinatorial immunotherapies are getting much acceptance as a way to improve therapeutic outcomes by blocking immunosuppressive signals in the tumour microenvironment (TME). The combination of Vascular Endothelial Growth Factor (VEGF) inhibitors with ICI resulted in significant synergistic effects in various preclinical and clinical studies. However, the adverse effects associated with current synthetic VEGF inhibitors limit its clinical utility. In this review, we have summarized the potential of phytochemicals, especially the category of flavonoids, alkaloids, glycosides, terpenoids, and coumarin, as the available-affordable-safe-effective repositories of VEGF inhibitors. Their possibilities as an alternative for synthetic VEGF inhibitors by synergistic combination with ICI are reviewed, thereby enhancing patient compliance and survival rates. This review highlights the demand for a detailed investigation of the plausible role of plant-based anti-angiogenic-immunotherapy combination against HCC.
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Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab.
Khan, M, Aziz, AA, Shafi, NA, Abbas, T, Khanani, AM
Cells. 2020;(8)
Abstract
This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.
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Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
Staiano, RI, Loffredo, S, Borriello, F, Iannotti, FA, Piscitelli, F, Orlando, P, Secondo, A, Granata, F, Lepore, MT, Fiorelli, A, et al
Journal of leukocyte biology. 2016;(4):531-40
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Abstract
Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.
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The role of tumor-associated macrophages in breast cancer progression (review).
Obeid, E, Nanda, R, Fu, YX, Olopade, OI
International journal of oncology. 2013;(1):5-12
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Abstract
It is well established that the tumor microenvironment plays a major role in the aggressive behavior of malignant solid tumors. Among cell types associated with tumor microenvironment, tumor-associated macrophages (TAMs) are the most influential for tumor progression. Breast cancer is characterized by having a large population of TAMs, and experimental models have exposed multiple mechanisms by which TAMs interact with and influence the surrounding tumor cells. The process of metastasis involves tumor cells gaining access to the tissue outside the immediate tumor environment and invading the confining extracellular matrix (ECM). Supporting this process, TAMs secrete proangiogenic factors such as VEGF to build a network of vessels that provide nutrition for tumor cells, but also function as channels of transport into the ECM. Additionally, TAMs release factors to decrease the local pro-inflammatory antitumor response, suppressing it and providing a means of escape of the tumor cells. Similarly, hypoxia in the tumor microenvironment stimulates macrophages to further produce VEGF and suppress the T-cell immune responses, thus, enhancing the evasion of tumor cells and ultimately metastasis. Given the multiple roles of TAMS in breast cancer progression and metastasis, therapies targeting these cells are in development and demonstrate promising results.
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[Chances and risks of anti-VEGF therapy].
Ziemssen, F, Heiduschka, P, Peters, S, Grisanti, S, Schraermeyer, U
Klinische Monatsblatter fur Augenheilkunde. 2008;(9):770-8
Abstract
Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. Through regulation of haemodynamics, haematopoesis and the immune system, endocrinology and reparative processes, inhibition of VEGF can cause multiple adverse events. Previous data suggest that--even after intravitreal injection--systemic exposure might occur, thus bearing the risk of manifestation of side effects. Experience with intravenous administration of the antibody bevacizumab (Avastin) pointed to the potential consequences of a pan-VEGF blockade. The change of haemodynamic parameters implies a potential influence on the patient's morbidity. Studies already conducted during the approval process do not provide sufficient statistical power when evaluating whether systemic events significantly differ between the treatment and control groups. Retinal perfusion showed an altered vascular tone (change in vessel diameter) following anti-VEGF treatment. Physiological fenestration of the choroicapillaris is significantly reduced. Possible effects on the local oxygen supply in ischaemic tissue have to be considered. In contrast to destructive treatment modalities (laser, cryo), VEGF inhibitors promise the prompt and efficient response of retinal neovascularisation and the preservation of a better function (visual fields). The maturation of growing vessels (pericytes) and the secondary formation of membranes are limiting factors with regard to the time-point at which anti-VEGF therapy is most effective. A diligent use of the available drugs has to take into account which types of exudative retinopathy are showing no or only very limited response to the treatment.
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[Effect of Yishen capsule on serum vascular endothelial growth factor and cell immunity in patients with chronic glomerulonephritis].
Wu, XL, Sun, WS, Zhang, WG, Qiao, CL, Wang, Z, Wang, J
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2007;(22):2416-8
Abstract
OBJECTIVE To explore the effect of Yishen capsule on the serum vascular endothelial growth factor (VEGF), the cell immunity and the theraphic. METHOD Serum VEGF and T cell subsets were studied in 30 normal subjects and 83 patients before and after treatment. RESULT Compare with normal subjects, CD3, CD4, CD4/CD8 were decreased, CD8 and serum VEGF were increased obviously (P <0. 05 or P <0. 01). After three months treatment with YiShen capsule, CD4/CD8 was increased, CD8 and serum VEGF were decreased significantly (P <0.05 or P <0.01). CONCLUSION Yishen capsule can reduce the proteinuria, increase the function of immunity and improve the clinical symptom of patients with chronic glomerulonephritis, achieved the effects of allevating chronic glomerular sclerosis ultimately.