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PTP, one polysaccharide extracted from the roots of Polygala tenuifolia , has displayed anti-cancer activity in several types of ovarian cancer cells. This study aims to elucidate the structure of PTP and investigate its anticancer effects against SKOV3 xenograft tumor growth in BALB/c mice, as well as the underlying mechanisms involved. GC–MS and NMR data indicate that PTP has a backbone composed of 1,4,6-linked-β-Gal p , 1,4-linked-β-Gal p and 1,4-linked-β-Glc p , with non-reducing terminal 1-linked-α-Glc p attached to O-6 of 1,4,6-linked-β-Gal p . The tumor growth was suppressed in mice following two week’s PTP administration (10, 20 and 40 mg/kg) due to the induction of apoptosis, as detected by TUNEL assay. Moreover, lower serum VEGF and EGFR levels were observed in BALB/c mice treated with different doses of PTP when compared with that in untreated mice. Also, EGFR, VEGF, and CD34 were decreased in both transcript and protein levels in the tumor-bearing mice upon PTP treatment. Taken together, our data suggest that PTP appears to be a powerful chemopreventive agent for the patients with ovarian cancer, especially at advanced stage. [ABSTRACT FROM AUTHOR]

Apatinib, a novel small molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, was approved for metastatic gastric adenocarcinoma in China in Oct 2014. This is the first report on its use for advanced colorectal cancer as a kind of third-line therapy to date. Here we report two Chinese patients who presented with metastatic colorectal cancer who received apatinib 850 mg daily as a third-line therapy. Both the patients achieved favorable benefits in outcomes after the administration of apatinib. Patient 1 benefited 4 months progression-free survival and 11 months overall survival, while patient 2's progression-free survival was over 10 months. Both the patients presented hand-foot syndrome, and one of them suffered a slight impairment of liver function, mild elevated blood pressure, and proteinuria. But these adverse events were manageable with symptomatic treatment and dose reduction or a short-time drug withdrawal. [ABSTRACT FROM AUTHOR]

The diagnosis of a glioblastoma is mainly made on the basis of their microscopic appearance with the additional determination of epigenetic as well as mutational analyses as deemed appropriate and taken into account in different centers. How far the recent discovery of tumor networks will stimulate novel treatments is a subject of intensive research. A tissue diagnosis is the mainstay. Regardless of age, patients should undergo a maximal safe resection. Magnetic resonance imaging is the surrogate parameter of choice for follow up. Patients should receive chemoradiotherapy with temozolomide with the radiation schedule adapted to performance status, age and tumor location. The use of temozolomide may be reconsidered according to methylguanine DNA methyltransferase (MGMT) promoter methylation status; patients with an active promoter may be subjected to a trial or further molecular work-up in order to potentially replace temozolomide; patients with an inactive (hypermethylated) MGMT promoter may be counseled for the co-treatment with the methylating and alkylating compound lomustine in addition to temozolomide. Tumor-treating fields are an additive option independent of the MGMT status. Determination of recurrence is still challenging. Patients with clinical or radiographic confirmed progression should be counseled for a second surgical intervention, that is, to reach another macroscopic removal of the tumor bulk or to obtain tissue for an updated molecular analysis. Immune therapeutic approaches may be dependent on tumor types and molecular signatures. In newly diagnosed and recurrent glioblastoma, bevacizumab prolongs progression-free survival without affecting overall survival in an unselected population of glioblastoma patients. Whether or not selection can be made on the basis of molecular or imaging parameters remains to be determined. Some patients may benefit from a second radiotherapy. In our view, the near future will provide support for translating the amazing progress in understanding the molecular background of glioblastoma in to more complex, but promising therapy concepts. [ABSTRACT FROM AUTHOR]

Fucoidan is a fucose-containing sulfated polysaccharide derived from brown seaweeds, crude extracts of which are commercially available as nutritional supplements. Recent studies have demonstrated antiproliferative, antiangiogenic, and anticancer properties of fucoidan in vitro. Accordingly, the anticancer effects of fucoidan have been shown to vary depending on its structure, while it can target multiple receptors or signaling molecules in various cell types, including tumor cells and immune cells. Low toxicity and the in vitro effects of fucoidan mentioned above make it a suitable agent for cancer prevention or treatment. However, preclinical development of natural marine products requires in vivo examination of purified compounds in animal tumor models. This review discusses the effects of systemic and local administration of fucoidan on tumor growth, angiogenesis, and immune reaction and whether in vivo and in vitro results are likely applicable to the development of fucoidan as a marine anticancer drug.

Abstracts Purpose: Pirfenidone is mostly used in antifibrotic and anti-inflammatory therapies. We have previously demonstrated that pirfenidone had antifibrotic and anti-inflammatory effects on the wound healing process after glaucoma filtration surgery in vitro and in vivo. Since the wound healing and reactive scarring process simultaneously involves inflammation, fibrosis, and angiogenesis, and angiogenesis plays a more important role in chronic or prolonged wound healing, we tried to explore the antiangiogenesis effect in pirfenidone and its potential multitarget function in regulating excessive scarring. The aim of the present study was to investigate the antiangiogenesis effect of pirfenidone.Methods: The proliferation of human umbilical vein endothelial cells (HUVECs) and human Tenon's fibroblasts (HTFs) were detected by WST-1 assay. The cell viability of HUVECs was measured by Trypan Blue together with lactate dehydrogenase, Annexin 5 experiment, and Ki-67 immunofluorescence assay. The functions of HUVECs and HTFs were demonstrated using cell migration assay, transwell invasion assay, and tube formation assay. The expression levels of vascular endothelial growth factor-A (VEGF-A), VEGF receptor-2 (VEGFR-2), neuropilin-1(NRP-1), and their downstream signaling proteins p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mechanistic target of rapamycin (mTOR) were indicated by western blot assay. The secretion of VEGF-A was detected by enzyme-linked immunosorbent assay.Results: Pirfenidone inhibited proliferation, migration, invasion, and tube formation of HUVECs in vitro, and had an equivalent antiangiogenesis effect when compared with Ranibizumab in HUVECs and HTFs. Pirfenidone downregulated VEGF-A/VEGFR-2, VEGF-A/NRP-1, and its downstream signaling pathway protein expression.Conclusions: Pirfenidone has an antiangiogenesis effect in the wound healing process and may become an ideal multitarget antiscarring agent after glaucoma filtration surgery. [ABSTRACT FROM AUTHOR]

2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11α-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ERα and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC 50 (2.73 μM −7.75 μM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 μM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment. [ABSTRACT FROM AUTHOR]

Antiangiogenic therapy has a proven survival benefit in metastatic colorectal cancer. Inhibition of the VEGF pathway using a variety of extracellular antibody approaches has clear benefit in combination with chemotherapy, while intracellular blockade using tyrosine kinase inhibitors (TKIs) such as sorafenib and regorafenib has had more limited success. Pharmacodynamic modeling using modalities such as DCE-MRI indicates potent antiangiogenic effects of these TKIs, yet numerous combination therapies, primarily with chemotherapy, have failed to demonstrate an additive benefit. The sole comparative study of a single agent TKI against placebo showed a survival benefit of regorafenib in patients with advanced, refractory disease. Preclinical data demonstrate synergy between antiantiogenic TKIs and targeted interventions including autophagy inhibition, and together with a renewed effort to define markers of susceptibility, such combinations may be a way to improve the limited efficacy of this once-promising drug class. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer is the leading cause of death from gynecologic tumors in western countries. Newly diagnosed epithelial ovarian cancer patients usually have good initial response to combination of platinum-based and taxane-based chemotherapy. However, most patients eventually experience relapses, and responses to subsequent therapies are generally short-lived. Intraperitoneal chemotherapy has been shown to improve survival outcomes, but toxicities and logistics limit its acceptance. Dose-dense schedule of paclitaxel combined with carboplatin remains controversial, and more studies are needed to validate this approach. About 15% of epithelial ovarian cancer patients carry gene mutations in BRCA1 and/or BRCA2. The development of poly(adenosine diphosphate-ribose) polymerase inhibitors represents a novel therapeutic strategy, in which poly(adenosine diphosphate-ribose) inhibition leads to the formation of double-stranded DNA breaks that cannot be accurately repaired in BRCA1- or BRCA2-mutated tumors, thus leading to tumor cell death. This principle of synthetic lethality can be demonstrated by olaparib, an oral agent that inhibits the repair of single strand DNA breaks during DNA replication, causing defective homologous recombination and hence tumor cell death. Currently, many poly(adenosine diphosphate-ribose) inhibitors are in different phases of development. Furthermore, mechanisms of defective homologous recombination pathway may include other genetic and epigenetic abnormalities in addition to either germline or somatic BRCA1 and/or BRCA2 mutations, making these pathways as potential therapeutic targets. The clinical pharmacology, clinical efficacy, safety, administration issues of olaparib and current clinical development of poly(adenosine diphosphate-ribose) inhibitors are described in this article, along with an overview on the treatment options (including intraperitoneal chemotherapy and dose-dense chemotherapy) for epithelial ovarian cancer. On the other hand, overexpression of the vascular endothelial growth factor and increased angiogenesis are associated with the development and progression of epithelial ovarian cancer. Although there are some expected toxicities associated with antiangiogenesis, combination of bevacizumab and systemic chemotherapy improves the progression-free survival and response rate compared to chemotherapy alone. The clinical efficacy of adding bevacizumab and its safety for advanced epithelial ovarian cancer is also reviewed, with emerging data on antiangiogenesis therapy. [ABSTRACT FROM AUTHOR]

Recent reports have revealed that hydrogen sulfide (H2S) exerts critical actions to promote cardiovascular homeostasis and health. Thiosulfate is one of the products formed during oxidative H2S metabolism, and thiosulfate has been used extensively and safely to treat calcific uremic arteriopathy in dialysis patients. Yet despite its significance, fundamental questions regarding how thiosulfate and H2S interact during redox signaling remain unanswered. In the present study, we examined the effect of exogenous thiosulfate on hypoxiainduced H2S metabolite bioavailability in human umbilical vein endothelial cells (HUVECs). Under hypoxic conditions, we observed a decrease of GSH and GSSG levels in HUVECs at 0.5 and 4 h as well as decreased free H2S and acid-labile sulfide and increased bound sulfide at all time points. Treatment with exogenous thiosulfate significantly decreased the ratio of GSH/GSSG to total sulfide of HUVECs under 0.5 h of hypoxia but significantly increased this ratio in HUVECs under 4 h of hypoxia. These responses reveal that thiosulfate has different effects at low and high doses and under different O2 tensions. In addition, treatment with thiosulfate also diminished VEGF-induced cystathionine-γ-lyase expression and reduced VEGF-induced HUVEC proliferation under both normoxic and hypoxic conditions. These results indicate that thiosulfate can modulate H2S metabolites and signaling under various culture conditions that impact angiogenic activity. Thus, thiosulfate may serve as a unique sulfide donor to modulate endothelial responses under pathophysiological conditions involving angiogenesis. [ABSTRACT FROM AUTHOR]

We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). Studies using such models, and others including transplanted cell lines, often yield highly encouraging results which are seldom recapitulated in the clinic, especially when assessed in randomized phase III clinical trials. While there are likely many different reasons for this discrepancy, one is likely the failure to recapitulate treatment of advanced visceral metastatic disease in mice. With this gap in mind, we have developed a number of models of metastatic human tumor xenografts (and more recently, of mouse tumors in syngeneic immunocompetent mice). A pattern of response we have observed with various targeted agents, e.g. VEGF pathway targeting antiangiogenic drugs or trastuzumab, is effective when treating primary tumors in contrast to a complete or severely reduced lack of such efficacy when treating advanced metastatic disease. Interestingly, an exception to this pattern has been observed using various continuous low-dose metronomic chemotherapy regimens, where counterintuitively, superior responses are observed in the metastatic setting, as well as superiority or equivalence of metronomic chemotherapy over standard maximum tolerated dose (MTD) chemotherapy, with lesser toxicity. The basis for these encouraging results may be related to the multiple mechanisms responsible for the anti-tumor effects and longer duration of metronomic chemotherapy regimens made possible by lesser toxicity. These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems. [ABSTRACT FROM AUTHOR]

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Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Over the past decade, patients with advanced non-small-cell lung cancer (NSCLC) have witnessed substantial advances in regards to therapeutic alternatives. Among newly developed agents, angiogenesis inhibitors were extensively tested in different settings and have produced some favorable outcomes despite several shortcomings. Bevacizumab is the most examined agent in this context and has demonstrated significant survival benefits when combined with standard chemotherapy in eligible patients. Preliminary results on the addition of bevacizumab to erlotinib in patients with EGFRmutated NSCLC seem promising. Other antiangiogenic agents were also tested, but ramucirumab and nintedanib are the only agents with a positive impact on survival. More recently, immune checkpoint inhibitors (ICIs) have had considerable success due to their prolonged durations of response, yet response rates are still deemed suboptimal, and various combination therapies are being tested in an effort to improve efficacy. Preclinical evidence suggests an immunosuppressive effect of pro-angiogenic factors, which sets up a plausible rationale for combining ICIs and antiangiogenic agents. Herein, we review the landmark data supporting the success of angiogenesis inhibitors, and we discuss the potential for combination with immunotherapy and targeted agents. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the "inflammation-MMP9-angiogenesis" cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV., (© 2023 Wiley-VCH GmbH.)

Background: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535. Results: SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR) 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties. Conclusion: All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma.

Background and objective The aim of this study is to investigate difference of antiangiogenesis ablility and interaction about bevacizumab and endostatin in vivo in lung cancer animal model. Methods First, we construct a Balb/c mice model with A549 lung adenocarcinoma cell. Then, we divide the mice into four groups randomly. Every group has six mice. Control group: mice injected with normal saline every day aroud the tumor. Endostatin group: mice injected with endostatin (Recombinant endostatin) injection (3 mg/kg) every day Peritumoral. Bevacizumab group: mice injected with bevacizumab twice a week (biw/5 mg/kg) Peritumoral. Combing group: mice were injected with endostatin and bevacizumab (dose just like single drug group). After 16 days, we executed mice and got the tumor tissue for next analysis. Results Based on this experiment, we found bevacizumab and endostatin expressed the ability for inhibiting tumor growth in vivo. Bevacizumab was more powerful (52.36% vs 38.68%). Combining bevacizumab with endostatin could get better results (64.15%) than single drug did. Bevacizumab played the role by inhibiting VEGF-A expression (60.8%). Endostatin took effect by inhibiting VEGF-A/C (14.6%, 30.3%). Combining group present better antitumor efficacy than any single drug group did. (79.7%, 44.2%). Conclusion Both bevacizumab and endostatin present the antiangiogenesis ability in vivo of lung cancer animal model. In our test, bevacizumab show better ability in inhibiting tumor growth than endostatin does. Additional, combing bevacizumab with endostatin reveal better potential to inhibit tumor growth than single drug does.

Gambogic acid (GA) is in a phase II clinical trial as an antitumor and antiangiogenesis agent. In this study, 36 GA derivatives were synthesized and screened in a zebrafish model to evaluate their antiangiogenic activity and toxicity. Derivatives 4, 32, 35, 36 effectively suppressed the formation of newly grown blood vessels and showed lower toxicities than GA as evaluated by zebrafish heart rates and mortalities. They also exhibited more potent migration and HUVEC tube formation inhibiting activities than GA. Among them, 36 was the most potent one, suggesting that it may serve as a potential new antiangiogenesis candidate with low toxicity. Additionally, 36 showed comparable antiproliferative activity to HUVECs and five tumor cell lines but low cytotoxicity to LO2 cells.

We previously reported that smenospongine, a sesquiterpene aminoquinone isolated from the marine sponge Dactylospongia elegans, showed antiproliferative or cytotoxic activities on leukemia cells. In this study, we investigated the effect of smenospongine on solid tumors. Since angiogenesis is well known to be closely involved in growth and metastasis of solid tumors, the antiangiogenic effect of smenospongine was determined. We found that smenospongine inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Moreover, the inhibitory activity of smenospongine on growth of solid tumor cells was investigated. Smenospongine inhibited the growth of 39 human solid cancer cells in vitro, with a mean Log GI50 value of −5.55. In conclusion, smenospongine exhibits antitumor activity on solid tumors via two mechanisms, an antiangiogenic effect on endothelial cells and direct inhibition of growth of tumor cells.

Molecular plant components have long been aimed at the angiogenesis and anti-angiogenesis pathways, and have been tested as sources for antineoplasic drugs with promising success. The present work deals with the anti-angiogenic effects of Methyl Jasmonate. Jasmonate derivatives were demonstrated to selectively damage the mitochondria of cancer cells. In vitro, 1-10 mM Methyl Jasmonate induced the cell death of the human umbilical vein endothelial cells (HUVEC) and the Murine melanoma cells (B16F10), while micromolar concentrations were ineffective. In vivo, comparable concentrations were toxic and reduced the vessel density of the Chorioallantoic Membrane of the Chicken Embryo (CAM). However, 1-10 µM concentrations produced a complex effect. There was increased capillary budding, but the new vessels were leakier and less organised than corresponding controls. It is suggested that not only direct toxicity, but also the drug effects upon angiogenesis are relevant to the antineoplasic effects of Methyl Jasmonate.Moléculas de origem vegetal são, há muito, conhecidas como substâncias ativas sobre as vias de angiogênese e antiangiogênese e foram testadas como fonte de drogas antineoplásicas com sucesso promissor. Este trabalho trata dos efeitos antiangiogênicos do Metiljasmonato, um protótipo da família dos derivados do ácido jasmônico, que danificam seletivamente a mitocôndria de células neoplásicas. In vitro, metiljasmonato 1-10 mM promoveu a morte celular de células endoteliais humanas de cordão umbilical (HUVEC) e de melanoma murino (B16F10); concentrações micromolares foram inócuas. In vivo, concentrações equivalentes foram tóxicas e reduziram a densidade de vasos em membranas corioalantoicas de embrião de galinha (CAM). Entretanto, concentrações entre 1-10 µM produziram um efeito complexo. Ocorreu aumento no brotamento capilar, mas os novos vasos apresentaram-se frágeis e menos organizados que os controles correspondentes. Sugere-se que, além da toxicidade direta contra as células tumorais, a ação do metiljasmonato sobre a angiogênese seja relevante para seu efeito antineoplásico.

Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but rather they are selective against a limited number of tyrosine kinases. The success of imatinib-mesylate (Gleevec®) for the treatment of patients with chronic myeloid leukemia has opened a intensive search for new small molecular compounds able to target other protein tyrosine kinases involved in the malignant transformation. This review article is focused on the use of tyrosine kinase inhibitors as antiangiogenic molecules in the treatment of multiple myeloma.

Antiangiogenesis, e.g., inhibition of blood vessel growth, is being investigated as a way to prevent the growth of tumors and other angiogenesis-dependent diseases. Pharmacological inhibition interferes with the angiogenic cascade or the immature neovasculature with synthetic or semi-synthetic substances, endogenous inhibitors or biological antagonists.The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane, which serves as a gas exchange surface and its function is supported by a dense capillary network. Because its extensive vascularization and easy accessibility, CAM has been used to study morphofunctional aspects of the angiogenesis process in vivo and to study the efficacy and mechanism of action of pro- and anti-angiogenic molecules. The fields of application of CAM in the study of antiangiogenesis, including our personal experience, are illustrated in this review article.

Background and objective Antiangiogenesis has become the fourth module of cancer therapy nowadays. However, its clinical effect varies from cancer to cancer. The aim of this study is to compare the clinical efficacy of rh-endostatin (YH-16, Endostar) on retreated non-small cell lung cancer and colorectal cancer. Methods The patients including 17 cases of retreated non-small cell lung cancer (NSCLC) and 15 cases of retreated colorectal cancer were confirmed by histopathology or cytopathology. All the cases were administrated with rh-endostatin combining chemotherapy and radiotherapy. 7.5 mg/m2 rhendostatin solved in 500 mL of normal saline was slow intravenously dropped from day 1 to day 14. The efficacy was evaluated strictly according to RECIST criteria and the quality of life (QOL) was based on the Karnofsky performance (KPS). Results The response rate (RR) of 17 cases of retreated NSCLC was 11.8% (2/17), and the disease control rate (DCR) was 41.2% (7/17). However, the RR and DCR of the 15 cases of retreated colorectal cancer were up to 40% (6/15) and 86.6% (13/15). There was significant difference between these two tumors (P < 0.05). Moreover, significant difference was also found on the QOL of these two tumors [The improving and stable QOL was 41.2% (7/17) and 86.6% (13/15), respectively (P < 0.05)]. Conclusion The clinical efficacy of rh-endostatin on retreated colorectal cancer was better than on retreated non-small cell lung cancer, which suggested that it was necessary to perform more clinical observations on the digestive tumors.

The medicinal properties of natural/edible plant products and their use are popular in traditional practice owing to their nutritional contents with little to no side effects. Lepista nuda (L. nuda), an edible mushroom (Clitocybe nuda, commonly known as blewit), has attracted researchers to evaluate its contents and the mechanism of its activities. In the current study, we focused on evaluating the antiangiogenic effects of L. nuda water extract on zebrafish development and in vitro human umbilical vein endothelial cell (HUVEC) tube formation. Bioactive components such as ergothioneine, eritadenine, and adenosine were identified and quantified by HPLC analysis. The L. nuda extract showed antiangiogenic properties and inhibited intersegmental vessel (ISV), caudal vein plexus (CVP), hyaloid vessel (HV), and subintestinal vessel (SIV) development in Tg (fli1: EGFP) zebrafish embryos. The expression of angiogenesis-related genes (vegfaa, kdrl, vegfba, flt1, kdr) was affected following L. nuda extract treatment. L. nuda extract attenuated in vitro HUVEC tube formation, migration, and invasion. Furthermore, inhibition of MAPK/p38 signaling and depletion of proangiogenic genes, including growth factors (fgf, ang2, and vegfa); primary and accessory receptors (tie2, vegfr2, and eng); MMPs (mmp1 and mmp2); and cytokines (il-1α, il-1β, il-6, and tnf-α) was observed in HUVECs following L. nuda treatment. An in vivo zebrafish xenograft assay showed that L. nuda extract inhibited HuCCT1 cell-induced SIV sprouting in HuCCT1-injected embryos. Collectively, the results suggest that L. nuda could be a potential inhibitor of angiogenesis limiting cancer progression. • Ergothioneine, eritadenine, and adenosine identified as potential bioactive components in L. nuda extract. • L. nuda extract attenuates developmental angiogenesis in zebrafish embryos through depletion of pro-angiogenic genes. • L. nuda inhibits/delays the development of ISV, SIV, CVP, and HV in zebrafish embryos. • L. nuda attenuates HUVEC tube formation through inhibition of the MAPK/p38 signaling axis. • L. nuda inhibits HuCCT1 tumor cell-induced SIV sprouting and tumor proliferation in zebrafish xenografts. [ABSTRACT FROM AUTHOR]

The application of photodynamic therapy has become more and more important in combating cancer. However, the high lipophilic nature of most photosensitizers limits their parenteral administration and leads to aggregation in the biological environment. To resolve this problem and deliver a photoactive form, the natural photosensitizer parietin (PTN) was encapsulated in poly(lactic-co-glycolic acid) nanoparticles (PTN NPs) by emulsification diffusion method. PTN NPs displayed a size of 193.70 nm and 157.31 nm, characterized by dynamic light scattering and atomic force microscopy, respectively. As the photoactivity of parietin is essential for therapy, the quantum yield of PTN NPs and the in vitro release were assessed. The antiproliferative activity, the intracellular generation of reactive oxygen species, mitochondrial potential depolarization, and lysosomal membrane permeabilization were evaluated in triple-negative breast cancer cells (MDA-MB-231 cells). At the same time, confocal laser scanning microscopy (CLSM) and flow cytometry were used to investigate the cellular uptake profile. In addition, the chorioallantoic membrane (CAM) was employed to evaluate the antiangiogenic effect microscopically. The spherical monomodal PTN NPs show a quantum yield of 0.4. The biological assessment on MDA-MB-231 cells revealed that free PTN and PTN NPs inhibited cell proliferation with IC 50 of 0.95 µM and 1.9 µM at 6 J/cm 2 , respectively, and this can be attributed to the intracellular uptake profile as proved by flow cytometry. Eventually, the CAM study illustrated that PTN NPs could reduce the number of angiogenic blood vessels and disrupt the vitality of xenografted tumors. In conclusion, PTN NPs are a promising anticancer strategy in vitro and might be a tool for fighting cancer in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Research into tumorigenic pathways can aid in the development of more efficient cancer therapies and provide insight into the physiological regulatory mechanisms employed by rapidly proliferating cancer cells. Due to the severe side effects of cancer chemotherapeutic medications, plant chemicals and their analogues are now explored more frequently for the treatment and prevention of colorectal cancer (CRC), opening the stage for new phytotherapeutic strategies that are considered effective and safe substitutes. Our study aimed to evaluate the medicinal properties of Withania somnifera L. and its safety applications in CRC management. Important databases were rigorously searched for relevant literature, and only 82 full-text publications matched the inclusion requirements from a massive collection of 10,002 titles and abstracts. W. somnifera L. contains a high concentration of active plant-based compounds. The pharmacological activity of the plant from our study has been demonstrated to exert antiproliferation, upregulation of apoptosis, decrease in oxidative stress, downregulation of cyclooxygenase-2 (COX-2), induction of targeted cytotoxic effects on cancerous cells, and exertion of both antiangiogenesis and antimigratory effects. We advise further research before recommending W. somnifera L. for clinical use to identify the optimal concentrations required to elicit beneficial effects in CRC management in humans, singly or in combination.

Jujuboside B (JuB), one of the main active triterpenoid saponins from the traditional Chinese medicine Ziziphus jujuba, possesses a wide range of pharmacological activities. However, it is unknown whether JuB can inhibit tumor angiogenesis, a crucial step in solid tumor growth. In this study, we found that JuB significantly inhibited the proliferation, migration, and tube formation of human umbilical vein endothelial cells in a dose-dependent manner. JuB also suppressed angiogenesis in chick embryo chorioallantoic membranes and Matrigel plugs. Moreover, through angiogenesis inhibition, JuB delayed the growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay demonstrated that JuB inhibited the phosphorylation of VEGFR2 and its key downstream protein kinases, such as Akt, FAK, Src, and PLCγ1. In conclusion, the antiangiogenic potency and molecular mechanism of JuB are revealed for the first time, indicating that this triterpene saponin may be further explored as a potential drug candidate or lead compound for antiangiogenic cancer therapy., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 The Author(s).)

Background: Suvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies., Patients and Methods: The phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3 + 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials., Results: All patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months)., Conclusions: Suvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer., Competing Interests: Disclosure Jiangsu Simcere Pharmaceuticals Co. Ltd., the sponsor of this trial, provided all trial costs, including investigational drugs, laboratory tests, and associated operational cost. WS, LL, YW, LS, XF, and JZ are full-time employees of Shandong Simcere Bio-Pharmaceutical Co., Ltd. Both Jiangsu Simcere Pharmaceuticals Co. Ltd. and Shandong Simcere Bio-Pharmaceutical Co., Ltd are subsidiaries of Simcere Pharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neoplastic cells often reside in distinctive tumor hypoxia armed with a series of adaptive responses including oxidative stress, defective apoptotic machinery and neoangiogenesis, through that further confer cell survival improvement. Plants still acts as reservoir of natural chemicals to provide newer active pharmacophores. Scutellarein is flavones which has wide range of pharmacophoral effects. In our current research, scutellarein employed for targeting oxidative stress mediated tumor angiogenesis and apoptotic nuclear fragmentation. Experimental results revealed that scutellarein has antiproliferative index against multiple cancer cell lines and diminished the oxidative stress and tumor development of murine ascitic lymphoma & inflammatory hepatocellular carcinoma. Eventual consequences lead to reduced neovessel formation by abrogating angiogeneic factors cytokine-VEGF-A, Flt-1, HIF-1α, MMP-2 and MMP-9 and reversing of evading apoptosis by activating caspase-3 activated DNA fragmentation factor (DFF-40) mediated nucleosomal degradation. In summary, our experimental evidences suggest that scutellarein has strong potentiality to attenuate the tumor development by modulating sprouting neovasculature and DFF-40 mediated apoptosis. [ABSTRACT FROM AUTHOR]

Background: Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The non-collagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic polypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine hepatocellular carcinoma models. In this study, we further explored the efficacy of Vastatin in the treatment of GB xenografts.Method: Treatment of Vastatin was carried out using a nanopolymer gene vector PEI600-CyD-Folate (H1). Antiangiogenic effect of Vastatin was tested in vitro by using co-culture system and conditioned medium. An orthotopic GB murine model was established to examine the in vivo therapeutic effect of Vastatin alone treatment and its combination with temozolomide.Results: Vastatin gene transfection mediated by H1 could target tumour cells specifically and suppress the proliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner. Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in GB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic polypeptide. The diminished presence of CD34 positive cells in the GB xenografts suggested that Vastatin induced significant antiangiogenesis. Moreover, a synergistic effect in extending survival was detected when H1-Vastatin was administered with temozolomide (TMZ) in GB chemoresistant murine models.Conclusion: Our results suggest, for the first time, that Vastatin is an antiangiogenic polypeptide with significant potential therapeutic benefit for GB. H1-Vastatin gene therapy may have important implications in re-sensitizing recurrent GB to standard chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Objective: The value of antiangiogenic inhibitors for patients with recurrent ovarian cancer has not been completely affirmed. Therefore, we aimed to assess the effectiveness and toxicities of various antiangiogenic drugs for the treatment of recurrent ovarian cancer. Methods: In this meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for complete randomized controlled trials. The searches were extended to May 15, 2016. The risk of bias of the included studies was evaluated via a Cochrane systematic evaluation, and the statistical analyses were performed using RevMan 5.2 software. Results: In total, we included 8 randomized controlled trials involving 3,211 patients and divided them into 3 groups, vascular endothelial growth factor receptor inhibitors (VEGFRIs), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), and angiopoietin inhibitors (trebananib). The progression-free survival improved significantly in all the groups being given antiangiogenic drugs (hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.45-0.67, I2=0%, P<0.00001 for the VEGFRI group; HR: 0.53, 95% CI: 0.45-0.63, I2=51%, P<0.00001 for the VEGF inhibitor group; HR: 0.67, 95% CI: 0.58-0.77, I2=0%, P<0.00001 for the trebananib group). Overall survival was obviously prolonged in the VEGFRI (HR: 0.76, 95% CI: 0.59-0.97, I2=0%, P=0.03), the VEGF inhibitor (HR: 0.87, 95% CI: 0.77-0.99, I2=0%, P=0.03), and trebananib groups (HR: 0.81, 95% CI: 0.67-0.99, I2=0%, P=0.04). The incidence of grade 3/4 side effects was different among the 3 groups, for example, proteinuria, hypertension, gastrointestinal perforation, and arterial thromboembolism were presented in the VEGF inhibitor group. Increased incidences of fatigue, diarrhea, and hypertension were seen in the VEGFRI group, and the trebananib group had a higher incidence of hypokalemia. Conclusion: This meta-analysis showed that antiangiogenic drugs improved the progressionfree survival. The VEGFRI, bevacizumab, and trebananib groups showed increased overall survival. Adding antiangiogenic drugs to chemotherapy treatment resulted in a higher incidence of grade 3/4 side effects, but these were manageable. [ABSTRACT FROM AUTHOR]

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for tumor growth and mediated mainly by vascular endothelial growth factor (VEGF) signaling. Inhibition of the VEGF signaling pathway has emerged as one of the promising approaches for cancer therapy. VEGF receptor 2 (VEGFR-2) is considered as a major mediator of angiogenic effects of VEGF. We describe herein the discovery of a series of potent VEGFR-2 tyrosine kinase (KDR) inhibitors from a new 2-(2-aminopyrimidin-4-yl)phenol scaffold. The KDR activity was reduced appreciably by a series of compounds with a benzoyl group at position 4 of phenol ring. The structure-activity relationships for a series of (3-(2-aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl methanones revealed compound 9 (KDR IC50 = 25 nM) as the most potent inhibitor in the series. Compound 22 had a potent cellular activity on VEGF-induced HUVEC cell growth (IC50 < 0.1 μM) with high selectivity over HCT116. [ABSTRACT FROM AUTHOR]

Development of resistance to standard therapy and toxic side effects are the major challenges encountered in chemotherapy of colorectal cancer. Increasing evidence has shown the ability of natural products to overcome various challenging disorders. Since, the development of antibiotics, fungi have been shown to be a wide useful source of lead compounds for the development of new pharmaceuticals. Fungal secondary metabolites from extreme environments are remarkable due to their diverse components, which makes them interesting candidates for drug discovery. In order to discover novel active antimetastatic and antiangiogenic compounds, secondary metabolites of halotolerant Penicillium chrysogenum-1 isolated from Tuz Lake in Turkey and ethyl acetate extract of halotolerant P. chrysogenum-1 was prepared from the isolate of halotolerant P. chrysogenum-1 culture medium. Firstly, antioxidant activity of the extract was determined. Then cytotoxicity and cell proliferation were investigated by WST-1 assay and real-time cell analysis system-DP on human umbilical vein endothelial cells and colorectal carcinoma cells, respectively. Antiangiogenic effects on human umbilical vein endothelial cells were evaluated with cell migration and invasion assays by using real-time cell analysis system. Also, mRNA expression levels of metastasis and angiogenesis-related genes, VEGFA, VEGFB, EGFR, COX-10, ANGPT-1 and IL-8 were determined on both cell lines. Results indicated that halotolerant P. chrysogenum-1 extract exhibited significant antimetastatic and antiangiogenic effects. According to the real-time cell analysis system results, IC50 concentrations of halotolerant P. chrysogenum-1 extract on Caco-2 and human umbilical vein endothelial cells were calculated as 55.2 and 37.89 μg/ml, respectively for 72 h. These results indicated that the secondary metabolites of halotolerant P. chrysogenum-1 extract could have the potential as a preventive and therapeutic agent in metastatic cancer processes. [ABSTRACT FROM AUTHOR]

Over the last decades, the vast chemical and biodiversity of marine environment has been identified as an important source of new anticancer drugs. The evolution of marine life is a result of competition among microorganisms for space and nutrients in the marine environment, which drives marine microorganisms to generate diverse enzyme systems with unique properties to adapt to harsh conditions of ocean. Therefore, marine-derived sources offer novel enzymes endowed with extraordinary properties. Recent advances in cancer therapy have facilitated enzyme therapy as a promising tool. But, the available information on the use of enzymes derived from marine sources as therapeutic agents for cancer therapy is scanty. The potential utility of marine enzymes in cancer therapy will be discussed in this chapter. [ABSTRACT FROM AUTHOR]

Background. Kefir is a unique cultured product that contains beneficial probiotics. Kefir culture from other parts of the world exhibits numerous beneficial qualities such as anti-inflammatory, immunomodulation, and anticancer effects. Nevertheless, kefir cultures from different parts of the world exert different effects because of variation in culture conditions and media. Breast cancer is the leading cancer in women, and metastasis is the major cause of death associated with breast cancer. The antimetastatic and antiangiogenic effects of kefir water made from kefir grains cultured in Malaysia were studied in 4T1 breast cancer cells. Methods. 4T1 cancer cells were treated with kefir water in vitro to assess its antimigration and anti-invasion effects. BALB/c mice were injected with 4T1 cancer cells and treated orally with kefir water for 28 days. Results. Kefir water was cytotoxic toward 4T1 cells at IC50 (half-maximal inhibitory concentration) of 12.5 and 8.33 mg/mL for 48 and 72 hours, respectively. A significant reduction in tumor size and weight (0.9132 ± 0.219 g) and a substantial increase in helper T cells (5-fold) and cytotoxic T cells (7-fold) were observed in the kefir water–treated group. Proinflammatory and proangiogenic markers were significantly reduced in the kefir water–treated group. Conclusions. Kefir water inhibited tumor proliferation in vitro and in vivo mainly through cancer cell apoptosis, immunomodulation by stimulating T helper cells and cytotoxic T cells, and anti-inflammatory, antimetastatic, and antiangiogenesis effects. This study brought out the potential of the probiotic beverage kefir water in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumabcontaining therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93].We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). Patients and methods: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and thirdline PFS, OS, HRQoL and safety. Results: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. Conclusions: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved secondline PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. [ABSTRACT FROM AUTHOR]

Lifestyle and dietary modifications have contributed much to somatic genetic alteration which has concomitantly led to increase in malignant diseases. Henceforth, plant based and dietary interventions to mitigate and impede oncogenic transformation are in great demand. We investigated the latex sap (LSL) of the dietary Lagenaria siceraria vegetable, the first domesticated plant species with the potent lectin activity for its functional role against the tumor progression and its mechanism. LSL has markedly stimulated proliferation of lymphocytes and displayed strong cytotoxic activity against cancer both in-vitro and in-vivo . The tumor regression was paralleled with drastic reduction in tumoral neovasculature as evidenced from angiogenic parameters and abrogated related gene expressions. LSL has also triggered apoptotic signaling cascade in cancer cells through activation of caspase-3 mediated activation of endonuclease and inducing apoptotic cellular events. Collectively our study provides tangible evidences that latex sap from L. siceraria with immunopotentiating ability significantly regresses the tumor progression by targeting angiogenesis and inducing cell death. [ABSTRACT FROM AUTHOR]

Natural compounds have been known as biosafety agents for their significant clinical and biological activity against dreadful diseases, including cancer, cardiovascular, and neurodegenerative disorders. Gambogic acid (GA), a naturally occurring xanthone-based moiety, reported from Garcinia hanburyi tree, is known to perform numerous intracellular and extracellular actions, including programmed cell death, autophagy, cell cycle arrest, antiangiogenesis, antimetastatic, and anti-inflammatory activities. In addition, GA-based synergistic approaches have been proven to enhance the healing strength of existing chemotherapeutic agents along with lesser side effects. The present review uncovers the bio-therapeutic potential of gambogic acid along with the possible mechanistic interactions of GA with its recognized cellular targets. [ABSTRACT FROM AUTHOR]

Imaging-guided photothermal therapy (PTT) has promising application for treating tumors. Nevertheless, so far imaging-guided photothermal drug-delivery systems have been developed with limited success for tumor chemo-photothermal therapy. In this study, as the proof-of-concept, a stimuli-responsive tumor-targeting rapamycin/DiR loaded lipid-polyaniline nanoparticle (RDLPNP) for dual-modal imaging-guided enhanced PTT efficacy is reported for the first time. In this system, polyaniline (PANI) with π-π electronic conjugated system and effective photothermal efficiency is chosen as the appropriate model receptor of fluorescence resonance energy transfer (FRET), and loaded cyanine probe (e.g., 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide, DiR) acts as the donor of near-infrared fluorescence (NIRF). In addition, rapamycin (RAPA), which is used as the antiangiogenesis chemotherapeutic drug, can cutdown the tumor vessels and delay tumor growth obviously. After intravenous treatment of RDLPNPs into Hela tumor bearing mice, fluorescent (from DiR) and enhanced photoacoustic (from DLPNPs) signals were found in tumor site over time, which reached to peak at the 6 h time point. After irradiating with an NIR laser, a good anti-tumor effect was observed owing to the enhanced photothermal and antiangiogenic effect of RDLPNPs. These results show that the multifunctional nanoparticle can be used as a promising imaging-guided photothermal drug delivery nanoplatform for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: To identify a novel therapeutic agent for hepatocellular carcinoma (HCC), for which no promising therapeutic agent exists, we screened a panel of plants and found that Juniperus chinensis exhibited potential antiangiogenic and anti-HCC activities. We further investigated the antiangiogenic and anti-HCC effects of the active ingredient of J. chinensis extract, CBT-143-S-F6F7, both in vitro and in vivo. Methods: A tube formation assay conducted using human umbilical vein endothelial cells (HUVECs) was first performed to identify the active ingredient of CBT-143-S-F6F7. A series of angiogenesis studies, including HUVEC migration, Matrigel plug, and chorioallantoic membrane (CAM) assays, were then performed to confirm the effects of CBT-143-S-F6F7 on angiogenesis. The effects of CBT-143-S-F6F7 on tumor growth were investigated using a subcutaneous and orthotopic mouse model of HCC. In vitro studies were performed to investigate the effects of CBT-143-S-F6F7 on the cell cycle and apoptosis in HCC cells. Moreover, protein arrays for angiogenesis and apoptosis were used to discover biomarkers that may be influenced by CBT-143-S-F6F7. Finally, nuclear magnetic resonance analysis was conducted to identify the compounds of CBT-143-S-F6F7. Results: CBT-143-S-F6F7 showed significantly antiangiogenic activity in various assays, including HUVEC tube formation and migration, CAM, and Matrigel plug assays. In in vivo studies, gavage with CBT-143-S-F6F7 significantly repressed subcutaneous Huh7 tumor growth in severe combined immunodeficient (SCID) mice, and prolonged the survival of orthotopic Huh7 tumor-bearing SCID mice (a 40 % increase in median survival duration compared with the vehicle-treated mice). Immunohistochemical staining of subcutaneous Huh7 tumors in CBT-143-S-F6F7-treated mice showed a significantly decrease in the cell cycle regulatory protein cyclin D1, cellular proliferation marker Ki-67, and endothelial marker CD31. CBT-143-S-F6F7 caused arrest of the G2/M phase and induced Huh7 cell apoptosis, possibly contributing to the inhibition of HCC tumors. Protein array analysis revealed that several angiogenic and antiapoptotic factors were suppressed in CBT-143-S-F6F7-treated Huh7 cells. Finally, five compounds from CBT-143-S-F6F7 were identified. Conclusions: According to these results, we report for the first time the antiangiogenic and anti-HCC activities of CBT-143-S-F6F7, the active fractional extract of J. chinensis. We believe that CBT-143-S-F6F7 warrants further evaluation as a new anti-HCC drug. [ABSTRACT FROM AUTHOR]