Search Results (264)

Compelling clinical evidence strongly indicates that anti-angiogenesis therapeutics including Bevacizumab, a humanised anti-VEGF mAb, can alleviate the resistance to immunotherapy. We explored the direct modulation of Bevacizumab on endothelial cell (EC) immune response including surface expression of adhesion and MHC molecules and EC-elicited proliferation of immune cells under inflammatory conditions. Flow cytometry showed that addition of VEGF inhibited TNF-α stimulation of expression of ICAM-1 and VCAM-1 on HUVECs, whereas Bevacizumab enhanced this TNF-α-stimulated expression. The presence of MHC Class I on HUVECs was decreased by VEGF and increased by TNF-α, respectively. Bevacizumab reversed VEGF downregulation and promoted TNF-α upregulation of MHC class I expression, suggesting that anti-VEGF treatment can boost the endothelial immunological reaction, a prerequisite for immune cell trafficking. Functionally, real-time monitoring of the proliferation of human PBMCs co-cultured on HUVEC monolayers over 3 days showed opposing effects on the proliferation of PBMCs between VEGF and TNF-α. Consistently, Bevacizumab antagonised VEGF suppression and sensitized TNF-α activation of PBMC growth over the time course. In line with these findings, Bevacizumab increased the surface expression of CD69 on VEGF-treated T cells collected from PBMCs after 3-day co-cultures with HUVECs. Furthermore, the proliferation of CD3+, CD8+ and CD4+ T cells was promoted via Bevacizumab. Collectively, this study demonstrates that targeting VEGF can enhance the immune response of ECs required for T cell recruitment. Our findings provide insights to a deeper understanding of increased vascular inflammatory response conferred by anti-VEGF treatment in addition to inhibiting angiogenesis, which supports its favourable dual role in the positive immunological synergism with immunotherapy. Full article

Systemic cancer progression culminating in metastatic disease is implicitly dependent on tumour cell interactions with the vascular system. Indeed, different facets of the micro- and macro-vasculature can be regarded as rate-limiting ‘vascular checkpoints’ in the process of cancer dissemination. The underlying complex communication networks drive tumour neovascularization, angiogenesis, immunoregulation, activation of the coagulation system, angiocrine interactions, and non-angiogenic vascular responses across multiple cancer types. Yet, each cancer may represent a unique vascular interaction scenario raising a prospect of targeted modulation of blood and lymphatic vessels for therapeutic purposes, beyond the traditional notion of tumour anti-angiogenesis. While the emphasis of studies aiming to understand this circuitry has traditionally been on soluble, or ‘mono-molecular’ mediators, the rise of the particulate secretome encompassing heterogeneous subpopulations of extracellular vesicles (EVs; including exosomes) and particles (EPs) brings another dimension into the tumour–vascular communication web during the process of metastasis. EVs and EPs are nanosized cellular fragments, the unique nature of which lies in their ability to encapsulate, protect and deliver to target cells a range of bioactive molecular entities (proteins, RNA, DNA) assembled in ways that enable them to exert a wide spectrum of biological activities. EVs and EPs penetrate through biological barriers and are capable of intracellular uptake. Their emerging vascular functions in metastatic or infiltrative cancers are exemplified by their roles in pre-metastatic niche formation, thrombosis, vasectasia or angiocrine regulation of cancer stem cells. Here, we survey some of the related evidence supporting the biological, diagnostic and interventional significance of EVs/EPs (EVPs) in disseminated neoplastic disease. Full article

Purpose. Genetic engineering of mesenchymal stromal cells (MSCs) using viral vectors has emerged as a promising approach to enhance the efficacy of anti-angiogenic gene therapies. Umbilical cord-derived MSCs are an attractive cell source due to their easy accessibility and potential for genetic modification. Adeno-associated viruses (AAVs) have been utilized in clinical settings to deliver therapeutic genes due to its characteristic of transient integration into the genome. In this study, we investigated the efficacy of using recombinant AAV-engineered umbilical cord-derived MSCs overexpressing anti-angiogenic factor, hsFlt-1 (MSCs.hsFlt1). Methods. The plasmid containing the hsFlt-1 gene was cloned into the AAV2 target backbone and validated using Sanger sequencing. The transduction process was studied to determine the optimal conditions, including the effect of MOI, media serum percentage, and attachment of MSCs, to achieve higher transduction efficiency. The functionality of MSCs.hsFtl1 was analyzed using qPCR, ELISA, and tube formation assays. Results. MSCs.hsFtl1 transduced at an MOI of 1 × 10⁶ demonstrated high transduction efficiency and exhibited robust gene and protein expression of hsFlt-1. The results revealed significant inhibition of growth in human umbilical vein endothelial cells (HUVECs) using a remarkably low dose of MSCs.hsFlt1 at 12.3 ng/mL. This observed anti-angiogenic effect was comparable to the clinically used Bevacizumab. Conclusions. The anti-angiogenic potential of MSCs.hsFlt1 effectively demonstrated in this study suggests their promising utility for targeted anti-angiogenic gene therapy approaches. Full article

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve and prevent vision loss leading to blindness. Rifampicin, a small-molecule antibiotic, has previously been reported to exhibit anti-angiogenic properties and a topical safety profile that is well-tolerated. Based on this evidence, we investigated the feasibility of formulating rifamycin as an ophthalmic drop capable of delivering therapeutic concentrations to the posterior segment of the eye. Methods: Inhibition of neovascularization by administration of rifampicin was analyzed in the rat oxygen-induced retinopathy (OIR) and mouse laser-induced choroidal neovascularization (CNV) models. Pharmacokinetic (PK) studies were conducted in mice, rats, and rabbits by dosing various formulations containing rifampicin, and the compound was quantified by LC/MS analysis. Results: Results from dose escalation studies in the mouse laser-induced CNV model suggested the minimum effective dose of rifampicin required for inhibiting neovascularization in subretinal tissues to be 0.7 mg/kg, which is substantially lower than the 20 mg/kg dosage approved for infectious disease treatments. The previous studies did not report the minimum effective dose in the anti-angiogenesis effects. The effective area under the concentration-time curve (AUC) in the sub-retina was evaluated as 0.27 h·ng/mg. In rabbits, rifampicin was delivered to the sub-retina by a single topical application of various formulations in a dose-dependent manner. The topical application of the formulations containing 1% rifampicin, which was well-tolerated in clinical trials previously reported for ocular trachoma, achieved subretinal delivery approximately 2–32 times greater than the effective AUC. Plasma exposure of the compound by the topical application was evaluated to range approximately 0.5–10 ng/mL. Conclusions: Rifampicin was delivered to the sub-retina in rabbits with an efficiency greater than the effective dose required for inhibiting neovascularization. Limited amounts of plasma exposure by the topical application were detected. These results suggested the therapeutic potential of the rifampicin formulations for the topical treatment of exudative macular degeneration. Full article

Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. Among the prepared analogs, the pyridone analog 19 bearing a methyl group at C-2 and a hydroxyl group at C-4 showed potent and selective growth inhibitory activity against human umbilical vein endothelial cells (HUVECs, IC₅₀ = 0.001 µM, selective index over that against human epidermoid carcinoma KB3-1 cells = 6400), exceeding those of natural products. The analog 19 of oral administration exhibited excellent in vivo antitumor activity in mice subcutaneously inoculated with sarcoma S180 cells. Full article

Melanoma, a type of skin cancer originating from melanocytes, represents a significant public health concern according to the World Health Organization. It is one of the most commonly diagnosed cancers worldwide, particularly affecting populations in Europe and North America, with an increasing incidence in Asia. The rise emphasizes the need for diversified treatment approaches. Conventional treatments for melanoma, including immunotherapy, chemotherapy, and targeted therapies like the FDA-approved Opdivo and Relatlimab, often come with severe side effects and high relapse rates. Consequently, natural products have gained considerable attention for their potential to enhance therapeutic outcomes and reduce adverse effects. This systematic review evaluates the anti-cancer properties of natural products against melanoma, examining 52 studies from PubMed and Google Scholar. Our analysis focuses on the antioxidant, anti-angiogenesis, anti-metastatic, and apoptosis-inducing activities of these compounds, also discussing the regulatory factors involved. The findings advocate for intensified research into natural products as complementary agents in melanoma treatment, aiming to improve efficacy and patient quality of life. Further in vitro, in vivo, and clinical trials are essential to validate their effectiveness and integrate them into standard care protocols. Full article

Lung cancer is the second cause of death in the world, being the most common type of cancer. Conventional therapies are not always recommended due to the particularities of patients. Thus, there is a need to develop new anticancer therapeutic agents. Medicinal plants constitute a source of bioactive compounds with therapeutic potential in lung cancer. The purpose of our narrative review is to evaluate and summarize the main studies on the cytotoxic effects of ten medicinal plants and their extracts, volatile oils, and bioactive compounds. We have also included studies that reported protective effects of these natural products against chemotherapy-induced toxicity. Studies were identified by assessing five databases using specific keywords. The investigated natural products possess cytotoxic effects on lung cancer cell cultures. Several mechanisms of action have been proposed including cell death by apoptosis, necrosis or autophagy, cell cycle arrest, the modulation of signaling pathways (PI3K/Akt and MAPK), the inhibition of migration, invasion and metastasis, antiangiogenesis, and targeting inflammation. Different bioactive compounds exhibit protective effects against chemotherapy-induced toxicity. Studies have shown promising results. To develop new therapeutic agents useful in treating lung cancer, the plants included in this review should be more deeply investigated to reveal their molecular mechanisms of action. Full article

Angiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine Streptomyces-derived compound, and evaluated its potential as a VEGFR2 inhibitor. LA selectively inhibited the proliferation of human endothelial cells EA.hy926 and HUVEC while exhibiting minimal effects on normal fibroblasts and various tumor cells. LA induced S-phase cell cycle arrest and apoptosis in EA.hy926 cells, increasing apoptotic markers p53, Bax, and p21 and decreasing the anti-apoptotic protein Bcl-2, with these effects being further enhanced under VEGF stimulation. Additionally, LA suppressed VEGFR2 phosphorylation and its downstream signaling pathways, including Akt/mTOR/p70S6K, MEK/ERK, Src, FAK, and p38 MAPK, which are crucial for endothelial survival and angiogenesis. Molecular docking studies revealed that LA binds to both inactive (DFG-out, PDB: 4ASD) and active (DFG-in, PDB: 3B8R) VEGFR2 conformations, with a significantly stronger affinity for the active state (−107.96 kcal/mol) than the inactive state (−33.56 kcal/mol), suggesting its potential as a VEGFR2 kinase inhibitor. Functionally, LA significantly inhibited VEGF-induced endothelial migration, tube formation, and microvessel sprouting in both in vitro and ex vivo rat aortic ring assays. Additionally, LA reduced tumor-associated tube formation induced by human breast tumor cells (MDA-MB-231), indicating its potential to suppress VEGF-dependent tumor angiogenesis. These findings suggest that LA is a promising selective anti-angiogenic agent with potential therapeutic applications in angiogenesis-related diseases such as cancer. Full article

Background. Neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors that pose significant therapeutic challenges due to their potential for progression, metastasis, and hormonal syndromes. Somatostatin analogs (SSAs) have emerged as a cornerstone in NEN treatment, offering both antisecretory and antiproliferative effects by targeting somatostatin receptors (SSTRs). Despite their proven efficacy, intrinsic and acquired resistance mechanisms, including receptor downregulation, tumor heterogeneity, and microenvironmental influences, limit their long-term effectiveness. Recent advances, including high-dose SSA regimens and novel formulations, have aimed to optimize their therapeutic utility and address these limitations. Body of the review. This review explores the cellular and molecular mechanisms underlying the antitumor effects of SSAs, including receptor-mediated signaling pathways, cell cycle arrest, apoptosis induction, and antiangiogenesis. The role of SSAs in combination therapies with mTOR inhibitors and peptide receptor radionuclide therapy (PRRT) is analyzed, emphasizing their synergistic potential. Key clinical trials, such as RADIANT-2, EVERLAR, and NETTER-1, support the efficacy of these approaches, demonstrating improved outcomes when SSAs are combined with targeted agents or radiolabeled therapies. Emerging strategies include high-dose SSA regimens, particularly in progressive cases with low Ki67 indices. Finally, novel formulations, including oral octreotide, paltusotine, and subcutaneous depot formulations like CAM2029, offer improved pharmacokinetics, bioavailability, and patient adherence. Ongoing clinical trials, including SORENTO, further evaluate their efficacy and safety profiles. Conclusions. This paper provides a comprehensive analysis of the cellular and molecular mechanisms of SSAs. SSAs remain integral to the management of NENs, providing effective tumor stabilization and symptom control. However, resistance mechanisms and tumor heterogeneity necessitate innovative approaches, including high-dose regimens, combination strategies, and next-generation formulations. Future research should focus on refining these strategies to optimize patient outcomes, enhance long-term efficacy, and expand the therapeutic landscape for NENs. Full article

RNA nanoparticles, derived from the packaging RNA three-way junction motif (pRNA-3WJ) of the bacteriophage phi29 DNA packaging motor, have been demonstrated to be thermodynamically and chemically stable, with promise as a nanodelivery system. Background/Objectives: A previous study showed that RNA nanoparticles with antiangiogenic aptamers (anti-vascular endothelial growth factor (VEGF) and anti-angiopoietin-2 (Ang2) aptamers) inhibited cell proliferation via WST-1 assay. To further investigate the antiangiogenic potential of these RNA nanoparticles, a modified three-dimensional (3D) spheroid sprouting assay model of human umbilical vein endothelial cells was utilized in the present study. Methods: Three groups of RNA nanoparticles were evaluated, namely, pRNA-3WJ series, RNA square series (polygon-type RNA nanoparticles), and 8WJ series (multiple-way junction RNA nanoparticles), which were conjugated with a single anti-VEGF, the combination of one anti-VEGF and one anti-Ang2, or multiple anti-VEGF aptamers. The core scaffold RNA nanoparticles (without aptamers) were used as the references, and bevacizumab was used as the positive control. Results: The results demonstrated the inhibition effects of the RNA nanoparticles on endothelial cell tube formation at 67 nM in a 3D spheroid sprouting model. The results in the 3D spheroid sprouting assay are consistent with those of the WST-1 proliferation assays. Conclusions: Among the RNA nanoparticles evaluated, 3WJ-3VEGF and SQR-VEGF-Ang2 had inhibition effects equivalent to bevacizumab and were promising for anti-angiogenesis treatment. Full article

Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab’s efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% had RAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p = 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p = 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab’s efficacy. Full article

Hepatocellular carcinoma (HCC) is a prevalent malignant tumour worldwide. Depending on the stage of the tumour and liver function, a variety of treatment options are indicated. Traditional radiotherapy and chemotherapy are ineffective against HCC; however, the U.S. Food and Drug Administration (FDA) has approved radiofrequency ablation (RFA), surgical resection, and transarterial chemoembolization (TACE) for advanced HCC. On the other hand, liver transplantation is recommended in the early stages of the disease. Tyrosine kinase inhibitors (TKIs) like lenvatinib and sorafenib, immunotherapy and anti-angiogenesis therapy, including pembrolizumab, bevacizumab, tremelimumab, durvalumab, camrelizumab, and atezolizumab, are other treatment options for advanced HCC. Moreover, to maximize outcomes for patients with HCC, the combination of immune checkpoint inhibitors (ICIs) along with targeted therapies or local ablative therapy is being investigated. This review elaborates on the current status of HCC treatment, outlining the most recent clinical study results and novel approaches. Full article

Lung cancer is a prevalent and very aggressive sickness that will likely claim 1.8 million lives by 2022, with an estimated 2.2 million additional cases expected worldwide. The goal of the current investigation was to determine whether petroleum ether extract of purslane leaf could be used to treat lung cancer induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-buta-4 none (NNK) in rats. In the in vitro extract recorded, promising anticancer effects in A540 cell lines with IC₅₀ were close to the reference drug, doxorubicin (14.3 and 13.8 μg/mL, respectively). A dose of 500 mg/kg/day orally for 20 weeks exhibited recovery effects on NNK-induced lung cancer with a good safety margin, where Intercellular Adhesion Molecule-1 (ICAM-1), the lung cancer biomarker, was significantly reduced by about 18.75% compared to cancer control. Purslane exhibited many anticancer mechanisms, including (i) anti-proliferation as a significant reduction in Ki67 level (20.42%), (ii) anti-angiogenesis as evident by a considerable decrease in Matrix metalloproteinase-9 (MMP-9) expression (79%), (iii) anti-inflammation as a remarked decline in Insulin-like growth factor 1 (IGF-1) expression (62%), (iv) pro-apoptotic effect as a significant activation in Forkhead box protein O1 (FOXO1) expression (262%), and (v) anti-oxidation as remarkable activation on antioxidant biomarkers either non-enzymatic or enzymatic concurrent with considerable depletion on oxidative stress biomarker, in comparison to cancer control. The histopathological examination revealed that Purslane extract showed markedly improved tissue structure and reduced pathological changes across all examined organs caused by NNK. The anti-lung cancer effect exhibited by the extract may be linked to the active ingredients of the extract that were characterized by LC–MS, such as α-linolenic acid, linoleic acid, palmitic acid, β-sitosterol, and alkaloids (berberine and magnoflorine). Full article

Background and Objectives: Cervical cancer is the third leading cause of cancer-related mortality in females. One of the most successful therapeutic modalities to date is suppressing vascular endothelial growth factor (VEGF)-mediated angiogenesis. Bevacizumab is a monoclonal antibody that targets VEGF-A. The outcomes for cervical cancer patients treated with bevacizumab in combination with platinum-based chemotherapy have been explored in several studies. This study aimed to assess the impact of bevacizumab on progression-free survival (PFS) and overall survival (OS) in patients with metastatic cervical cancer. Materials and Methods: This systematic review was registered in PROSPERO (CRD42023456755). Following PRISMA guidelines, a comprehensive literature search on PubMed and Google Scholar identified 28 studies meeting the inclusion criteria. The outcomes of interest were PFS and OS. The statistical analysis computed hazard ratios (HRs) with 95% confidence intervals (CIs). The study also included a subgroup analysis by cervical cancer stage. Results: The pooled analysis revealed that bevacizumab-based therapy significantly improved both PFS with HR 0.77 (95% CI: 0.58–0.96; p < 0.01; I² = 58%) and OS with HR 0.63 (95% CI: 0.45–0.89; p < 0.01; I² = 41%) in cervical cancer patients. Subgroup analysis by stage of cervical cancer demonstrated better efficacy of bevacizumab in metastatic stage IVB cervical cancer patients indicated by HR for PFS (0.69, 95% CI: 0.54–0.79; p < 0.01) and HR for OS (0.57, 95% CI: 0.46–0.73; p < 0.01). Conclusions: Bevacizumab exhibits a significant increase in PFS and OS, underscoring the efficacy of anti-angiogenesis therapy in cervical cancer, particularly in stage IVB metastatic cervical cancer patients. Full article