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Mini Reviews in Medicinal Chemistry 2016Angiogenesis is indispensible for tumor growth and metastasis. Antiangiogenic therapy is now a validated major strategy in cancer clinic; several small molecule... (Review)
Review
Angiogenesis is indispensible for tumor growth and metastasis. Antiangiogenic therapy is now a validated major strategy in cancer clinic; several small molecule angiogenic inhibitors have been successfully translated into clinic for multiple cancer indications. In the past decade, many natural products with potent antiangiogenic activity were explored and the underlying molecular mechanisms were revealed. One important mechanism is the inhibition of one or several steps in VEGF/VFGFR signaling pathway. Other factors (bFGF, HIF-1α, NF-κB etc.) capable of regulating angiogenesis, are also down-regulated by some natural products. Moreover, some of the antiangiogenic natural products also significantly inhibit vasculogenic mimicry (VM), another important vessel recruitment avenue in cancer, by regulating the key signaling of VM formation including VE-cadherin, EphA2, and Nodal signaling. In this mini-review, we summarized the natural products with suppressive effect on tumor angiogenesis and VM according to their diverse molecular mechanisms, and discussed the major direction of future research in this field.
Topics: Angiogenesis Inhibitors; Animals; Biological Products; Humans; Molecular Mimicry; Neoplasms; Neovascularization, Pathologic
PubMed: 26864555
DOI: 10.2174/1389557516666160211115507 -
Seminars in Cancer Biology Nov 2022Antiangiogenic therapies are considered a promising strategy against solid tumors. Their aim is to inhibit the formation of new blood vasculature, thereby reducing the... (Review)
Review
Antiangiogenic therapies are considered a promising strategy against solid tumors. Their aim is to inhibit the formation of new blood vasculature, thereby reducing the oxygen and nutrient supply to prevent further tumor growth and spreading. However, the strategy has seen limitations, as survival benefits are modest and often accompanied with increased tumor aggressiveness in form of invasion and metastasis. Antiangiogenic induced changes in the tumor microenvironment, such as hypoxia, mechanical stress or extracellular acidification can activate different receptors of tumoral and stromal cells and induce an extensive remodeling of the entire tumor microenvironment, with the overall goal to invade nearby tissues and regain access to the vasculature. In this regard, receptor tyrosine kinases have been studied intensively and especially the inhibition of c-Met has given promising results, characterized by a reduction in invasiveness and prolonged survival. Receptors that sense changes in the extracellular matrix like integrins or proteoglycans can also induce downstream signaling that stimulates the expression of remodeling factors such as new matrix components, enzymes or chemoattractants. Targeting multiple receptors and sensors of cancer cells simultaneously might represent an effective second line treatment that prevents the formation of malignant side effects.
Topics: Humans; Tumor Microenvironment; Angiogenesis Inhibitors; Extracellular Matrix; Neoplasms; Signal Transduction
PubMed: 35248730
DOI: 10.1016/j.semcancer.2022.03.003 -
Cancer Letters Sep 2017The search for small molecule inhibitors has gained prominence with the recognition of their inherent advantage for cancer therapy. Combretastatin is a naturally... (Review)
Review
The search for small molecule inhibitors has gained prominence with the recognition of their inherent advantage for cancer therapy. Combretastatin is a naturally occurring small stilbenoid. By virtue of the ability to bind to tubulin combretastatin and its derivatives promote depolymerisation of microtubules as well as inhibit tubulin polymerisation. This suppresses cell proliferation signalling and induces apoptosis. Combretastatins activate mitotic checkpoints that lead to mitotic catastrophe and apoptosis. They subvert the signalling systems which stimulate invasion, activate EMT (epithelial mesenchyme transition) and promote tumour progression. Allied with the ability to suppress angiogenesis these compounds have been viewed as potential inhibitors of metastasis. The notion of merging RTK (receptor tyrosine kinase) inhibition with suppression of invasion and possible inhibition of EMT has contributed to the credibility of combretastatins as anti-cancer agents. Invaluable are their attributes of inhibiting tumour growth and induction of apoptosis and necrosis by reducing blood supply to the tumour. Aside from these biological effects, this commentary also discusses the issues of the targeting of combretastatins to the tumour vasculature and effective delivery of the drugs encapsulated in nanospheres. Notwithstanding the perceived benefits, one can see a compelling need to understand the effects of combretastatin on the actin cytoskeletal dynamics and the disruption of microtubule polymerisation, and whether it is more efficient a tumour inhibitor than the conventional drugs that target microtubule dynamics. Combinations of combretastatins with other vascular disrupting agents have been attempted. It is essential to establish the perceived inhibition of EMT beyond reasonable doubt. This might justify using the combretastatins with allosteric EMT and Akt inhibitors as additional choices for pre-clinical/clinical studies.
Topics: Angiogenesis Inhibitors; Animals; Bibenzyls; Cell Movement; Cell Proliferation; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Burden
PubMed: 28688972
DOI: 10.1016/j.canlet.2017.06.032 -
Current Oncology Reports Apr 2022While vascular endothelial growth factor receptor inhibitors (VEGFRis) have dramatically improved cancer survival, these drugs cause hypertension in a majority of... (Review)
Review
PURPOSE OF REVIEW
While vascular endothelial growth factor receptor inhibitors (VEGFRis) have dramatically improved cancer survival, these drugs cause hypertension in a majority of patients. This side effect is often dose limiting and increases cardiovascular mortality in cancer survivors. This review summarizes recent advances in our understanding of the molecular mechanisms and clinical findings that impact management of VEGFRi-induced hypertension.
RECENT FINDINGS
Recent studies define new connections between endothelial dysfunction and VEGFRi-induced hypertension, including the balance between nitric oxide, oxidative stress, endothelin signaling, and prostaglandins and the potential role of microparticles, vascular smooth muscle cells, vascular stiffness, and microvessel rarefaction. Data implicating genetic polymorphisms that might identify patients at risk for VEGFRi-induced hypertension and the growing body of literature associating VEGFRi-induced hypertension with antitumor efficacy are reviewed. These recent advances have implications for the future of cardio-oncology clinics and the management of VEGFRi-induced hypertension.
Topics: Angiogenesis Inhibitors; Humans; Hypertension; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 35179707
DOI: 10.1007/s11912-022-01224-0 -
Future Oncology (London, England) Dec 2017Despite recent advances in metastatic lung cancer treatment with the advent of immune checkpoint inhibitors and molecules targeting addictive genomic abnormalities,... (Review)
Review
Despite recent advances in metastatic lung cancer treatment with the advent of immune checkpoint inhibitors and molecules targeting addictive genomic abnormalities, prognosis of most of the patients remains unfavorable. Combination approaches with older drugs, such as bevacizumab, should be thus envisioned. Bevacizumab is a monoclonal anti-VEGF antibody, approved by the US FDA and the EMA in first-line and maintenance settings of advanced nonsquamous non-small-cell lung cancer (NSCLC) treatment, in association with platinum-based chemotherapy. In the years to come, bevacizumab might be associated with new molecular therapies or immuno-oncology drugs, in order to optimize response rates and overcome resistances. This review summarizes the pharmacologic properties, clinical efficacy and safety of bevacizumab in advanced lung cancer treatment, with a focus on NSCLC, EGFR-mutant NSCLC and small-cell lung cancer.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Clinical Trials as Topic; Disease Progression; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Molecular Targeted Therapy; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Retreatment; Treatment Outcome
PubMed: 28812378
DOI: 10.2217/fon-2017-0302 -
PloS One 2016Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.
METHODS
Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).
RESULTS
A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.
CONCLUSIONS
In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
Topics: Angiogenesis Inhibitors; Bevacizumab; Glioblastoma; Humans; Recurrence; Salvage Therapy; Thalidomide
PubMed: 27007828
DOI: 10.1371/journal.pone.0152170 -
Marine Drugs Sep 2023Angiogenesis refers to the process of growing new blood vessels from pre-existing capillaries or post-capillary veins. This process plays a critical role in promoting...
Angiogenesis refers to the process of growing new blood vessels from pre-existing capillaries or post-capillary veins. This process plays a critical role in promoting tumorigenesis and metastasis. As a result, developing antiangiogenic agents has become an attractive strategy for tumor treatment. Sirtuin6 (SIRT6), a member of nicotinamide adenine (NAD)-dependent histone deacetylases, regulates various biological processes, including metabolism, oxidative stress, angiogenesis, and DNA damage and repair. Some SIRT6 inhibitors have been identified, but the effects of SIRT6 inhibitors on anti-angiogenesis have not been reported. We have identified a pyrrole-pyridinimidazole derivative as a highly effective inhibitor of SIRT6 and clarified its anti-pancreatic-cancer roles. This study investigated the antiangiogenic roles of . We found that was able to inhibit the migration and tube formation of HUVECs and downregulate the expression of angiogenesis-related proteins, including VEGF, HIF-1α, p-VEGFR2, and N-cadherin, and suppress the activation of AKT and ERK pathways. Additionally, significantly blocked angiogenesis in intersegmental vessels in zebrafish embryos. Notably, in a pancreatic cancer xenograft mouse model, down-regulated the expression of CD31, a marker protein of angiogenesis. These findings suggest that could be a promising antiangiogenic and cancer therapeutic agent.
Topics: Humans; Mice; Animals; Signal Transduction; Neovascularization, Pathologic; Zebrafish; Neoplasms; Angiogenesis Inhibitors; Sirtuins; Human Umbilical Vein Endothelial Cells
PubMed: 37888452
DOI: 10.3390/md21100517 -
Clinical Science (London, England :... May 2022Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria...
Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.
Topics: Angiogenesis Inhibitors; Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Endothelin-1; Epoprostenol; Female; Humans; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Rats; Vascular Endothelial Growth Factor A
PubMed: 35441670
DOI: 10.1042/CS20220182 -
Oxidative Medicine and Cellular... 2019Alkaloids are among the natural phytochemicals contained in functional foods and nutraceuticals and have been suggested for the prevention and/or management of oxidative... (Review)
Review
Alkaloids are among the natural phytochemicals contained in functional foods and nutraceuticals and have been suggested for the prevention and/or management of oxidative stress and inflammation-mediated diseases. In this review, we aimed to describe the effects of alkaloids in angiogenesis, the process playing a crucial role in tumor growth and invasion, whereby new vessels form. Antiangiogenic compounds including herbal ingredients, nonherbal alkaloids, and microRNAs can be used for the control and treatment of cancers. Several lines of evidence indicate that alkaloid-rich plants have several interesting features that effectively inhibit angiogenesis. In this review, we present valuable data on commonly used alkaloid substances as potential angiogenic inhibitors. Different herbal and nonherbal ingredients, introduced as antiangiogenesis agents, and their role in angiogenesis-dependent diseases are reviewed. Studies indicate that angiogenesis suppression is exerted through several mechanisms; however, further investigations are required to elucidate their precise molecular and cellular mechanisms, as well as potential side effects.
Topics: Alkaloids; Angiogenesis Inhibitors; Humans
PubMed: 31178979
DOI: 10.1155/2019/9475908 -
Toxicology and Applied Pharmacology Nov 2017Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis... (Review)
Review
Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis inhibition is one of the mechanisms by which melatonin exerts its oncostatic effects. Increased angiogenesis is a major feature of tumor progression, thus angiogenesis inhibition is a critical step in cancer therapy. Melatonin employs a variety of mechanisms to target nutrients and oxygen supply to cancer cells. At the transcriptional level, hypoxia induced factor-1α (HIF-1α) and the genes under its control, such as vascular endothelial growth factor (VEGF) are the main targets of melatonin for inhibition of angiogenesis. Melatonin prevents translocation of HIF-1α into the nucleus thereby hindering VEGF expression and also prevents the formation of HIF-1α, phospho-STAT3 and CBP/p300 complex which is involved in the expression of angiogenesis-related genes. Angiostatic properties of melatonin could be also due to its ability to inhibit VEGFR2's activation and expression. Other angiostatic mechanisms of melatonin include the inhibition of endothelial cell migration, invasion, and tube formation. In the present study, we have reviewed the molecular anti-angiogenesis pathways mediated by melatonin and the responsible mechanisms in various types of cancers both in vitro and in vivo.
Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Cell Movement; Cell Proliferation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Melatonin; Neoplasms; Neovascularization, Pathologic; Signal Transduction
PubMed: 28974455
DOI: 10.1016/j.taap.2017.09.022