AS1411 aptamer tagged PEGylated liposomes as a smart nanocarrier for tumor-specific delivery of Withaferin A for mitigating pulmonary metastasis.

Metastasis is the most challenging health problem contributing to about 90 % of cancer-related deaths worldwide. Metastatic tumors are highly aggressive and resistant to the most available therapeutic options. Hence, innovative therapeutic approaches are required to target metastatic tumors selectively. In this study, we prepared AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes (ALW) and investigated its therapeutic effect in B16F10 induced in pulmonary metastasis mice models. The prepared formulations' size and morphological properties were evaluated using dynamic light scattering system and Transmission electron microscope. ALW had spherical-shaped nanosized particles with a size of 118 nm and an encapsulation efficacy of 82.5 %. TEM analysis data indicated that ALW has excellent dispersibility and uniform spherical nano-size particles. ALW inhibited cell viability, and induced cell apoptosis of B16F10. In vivo, the pulmonary metastasis study in C57BL/6 mice revealed that the ALW significantly (p < 0.01) improved the encapsulated WA anti-metastatic activity and survival rate compared to WA or LW treated groups. ALW significantly (p < 0.01) downregulated the levels of IL-6, TNF-α, and IL-1ß and significantly reduced the lung collagen hydroxyproline, hexosamine, and uronic acid content in metastatic tumor bearing animals compared to WA or LW. Gene expression levels of MMPs and NF-κB were downregulated in ALW treated metastatic pulmonary tumor-bearing mice. These findings demonstrate that the AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes could be a promising nanoliposomal formulation for targeting metastatic tumors.

Inhibition of tumor-specific angiogenesis by AS1411 aptamer functionalized Withaferin A loaded PEGylated nanoliposomes by targeting nucleolin.

Angiogenesis is a vital process for tumor growth and metastasis. Inhibition of angiogenesis is a promising strategy in cancer treatment. In this study, we analyzed the anti-angiogenic activity of AS1411 functionalized Withaferin A encapsulated PEGylated nanoliposomes (ALW) using both in vitro and in vivo models. AS1411 aptamer functionalized nanoliposomes are an efficient drug delivery system for carrying chemotherapeutic agents to target cancer cells, and Withaferin A (WA) is a steroidal lactone known for potent anti-angiogenic activity. ALW showed significant inhibition in the migration and tube formation of endothelial cells, which are critical events in angiogenesis. In vivo angiogenesis study using ALW showed remarkable inhibition of tumor-directed capillary formation by altered serum cytokines, VEGF, GM-CSF, and NO levels. ALW treatment downregulated the gene expression of Matrix metalloproteinase (MMP)-2, MMP-9, VEGF, NF-kB and upregulated the expression of tissue inhibitor of metalloproteinase (TIMP)-1. Our results demonstrate that ALW inhibits tumor-specific angiogenesis by gene expression of NF-κB, VEGF, MMP-2, and MMP-9. The present study shows that using ALW can offer an attractive strategy for inhibiting tumor angiogenesis.

The Therapeutic Effects of Withaferin A against Cancer: Overview and Updates.

Cancer is a rapidly rising health problem among the global population, and this burden causes a significant challenge for public health. Current chemotherapeutic agents have different limitations, including drug resistance and severe side effects, and it demands a robust approach to accessing promising anti-cancer therapeutics. The natural compounds have been extensively studied to identify improved therapeutic agents for cancer therapy. Withaferin A (WA) is a steroidal lactone found in Withania somnifera and possesses anti-inflammatory, antioxidant, anti-angiogenesis, and anticancer properties. Multiple studies have shown that WA treatment attenuated various cancer hallmarks by inducing apoptosis and reducing angiogenesis and metastasis with reduced side effects. WA is a promising agent for the treatment of various cancer, and it targets various signaling pathways. With recent updates, the current review highlights the therapeutic implications of WA and its molecular targets in different cancer.

NF-κB as a Potential Target for the Treatment and Prevention of Mucositis.

Mucositis is a debilitating and severe side effect of chemotherapy and radiotherapy. It is responsible for reducing the patient's quality of life and represents a significant economic burden in oncology. Currently, there is no definitive and definite treatment for this disease. Intracellular signalling pathways have provided excellent drug development resources, particularly cancer therapeutic development. In recent decades, active research has been conducted to describe the pathogenesis of mucositis and the role of nuclear factor-kappa B (NF-κB) signalling pathways in mucositis development. Insights into the mechanisms of mucositis are creating new approaches for effective targeted treatment and their success in clinical use. Several studies have concentrated on elucidating the functional significance of NF-kB activation and its signalling mechanisms in mucositis in recent decades. Also, evidence indicates that NF-κB is the primary node for the development and progression of mucositis. Its altered expression is associated with increased mucosal injury in mucositis. Hence, regulating the activation of NF-κB could be a powerful strategy for the clinical management of mucositis. Thus, this review examines the role of NF-κB as a potential therapeutic target for chemotherapy and radiation-induced mucositis therapy.

NF-κB inhibitors in treatment and prevention of lung cancer.

Intracellular signalling pathways have provided excellent resource for drug development particularly in the development of cancer therapeutics. A wide variety of malignancies common in human exhibit aberrant NF-κB constitutive expression which results in tumorigenic processes and cancer survival in a variety of solid tumour, including pancreatic cancer, lung, cervical, prostate, breast and gastric carcinoma. Numerous evidences indicate that NF-κB signalling mechanism is mainly involved in the progression of several cancers which may intensify an enhanced knowledge on its role in disease particularly lung tumorigenesis. This has led to tremendous research in designing a variety of NF-κB antagonists with enhanced clinical applications through different approaches the most common being suppression of IκB kinase (IKK) beta activity. Many NF-κB inhibitors for lung cancer are now under clinical trials. Preliminary results of clinical trials for several of these agents include small-molecule inhibitors and monoclonal antibodies. A few combinatorial treatment therapies are currently under investigation in the clinics and have shown promise, particularly NF-κB inhibition associated with lung cancer.

Targeted inhibition of tumor survival, metastasis and angiogenesis by Acacia ferruginea mediated regulation of VEGF, inflammatory mediators, cytokine profile and inhibition of transcription factor activation.

Acacia ferruginea extract (AFE) was studied for anti-metastasis/-angiogenesis activity against B16F-10 melanoma cells in C57BL/6 mice. In vitro cytotoxicity of AFE was first screened using MTT assay and it was shown to inhibit B16F-10 cells with IC50 value of 52.94 µg/ml. Anti-metastatic activity of AFE in vivo revealed administration of AFE (10 mg/kg.b.wt) in three different regimens has shown reduced metastatic colony formation in lungs and prolonged survival in metastatic tumor-bearing hosts. Biochemical analysis shown that treatment with AFE significantly reduced the lung collagen hydroxyproline, hexosamine, uronic acid, sialic acid and gamma-glutamyl transpeptidase content. Administration of AFE significantly inhibited the iNOS and COX-2 level, diminished the infiltration of neoplastic cells and subsequently reduced the number of p53 and Bcl-2 positive immunoreactive cells as evidenced by histological and immunohistochemistry analysis. In addition, we found that, AFE significantly decreased the level of pro-inflammatory cytokines interleukin-1ß, IL-6, TNF-α and suppressed the nuclear factor kappa B (NF-κB) activation. Furthermore, angiogenesis studies shown significant reduction in number of tumor directed capillaries, regulating cytokines and vascular endothelial growth factor (VEGF). Our present results suggests that AFE could be a promising candidate for developing anti-cancer agents targeting metastasis which helps further to combat melanoma with effective treatment strategy.

Nephroprotective Effect of Bauhinia tomentosa Linn against Cisplatin-Induced Renal Damage.

Cisplatin (CP) is an important chemotherapeutic drug used for the treatment of a wide variety of solid tumors. However, clinical use of CP has been limited due to its adverse effect of nephrotoxicity. In the present study, we evaluate the nephroprotective effect of Bauhinia tomentosa against CP-induced renal damage in rats. Administration of methonolic extract of B. tomentosa (250 mg/kg b.w.) results in a significant increase in antioxidant enzymes including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Furthermore, treatment with B. tomentosa increased body weight and relative organ weight when compared with that of the CP-induced control group. Moreover, treatment with B. tomentosa extract significantly decreased lipid peroxidation(LPO), serum urea, and creatinine when compared with the CP-induced control group. Thus, the present study highlights the potential role of B. tomentosa and its use as a new protective strategy against CP-induced nephrotoxicity.

Acacia ferruginea inhibits inflammation by regulating inflammatory iNOS and COX-2.

Inflammation is a local defensive reaction of a host to cellular injury or infection. Prolonged inflammation can contribute to pathogenesis of many disorders. Identification of naturally occurring phytoconstituents that can suppress inflammatory mediators can lead to the discovery of anti-inflammatory therapeutics. Acacia ferruginea is used traditionally to treat numerous ailments including hemorrhage, irritable bowel syndrome and leprosy. The present study evaluated the anti-inflammatory activity of A. ferruginea extract against acute (carrageenan) and chronic (formaldehyde) inflammation in Balb/c mice. Pre-treatment with A. ferruginea extract (10 mg/kg BW) for 5 consecutive days via intraperitonial (IP) administration significantly inhibited subsequent induction of paw edema in both models; the effects were comparable to that of the standard drug indomethacin. The results also showed the A. ferruginea extract significantly inhibited nitric oxide (NO) synthesis and iNOS expression (as measured in serum), diminished inflammation in - and neutrophil infiltration to - the paw tissues and led to a reduction in the number of COX-2(+) immunoreative cells (as evidenced by histologic and immunohistochemical analyses) in the paws relative to those in paws of mice that received the irritants only. Further, in vitro studies showed the extract could significantly scavenge free radicals generated as in DPPH and NO radical generating assays. Taken together, the results showed that A. ferruginea extract imparted potent anti-oxidant and -inflammatory effects, in part by maintaining oxidative homeostasis, inhibiting NO synthesis and suppressing iNOS and COX-2 expression and so could potentially be exploited as a potential plant-based medication against inflammatory disorders.

Protective Effect of Solanum muricatum on Tumor Metastasis by Regulating Inflammatory Mediators and Nuclear Factor-Kappa B Subunits.

Metastasis is one of the hallmarks of malignant neoplasm or cancer, which is the leading cause of death in many cancer patients. A major challenge in cancer treatment is to find better ways to specifically target tumor metastases. In this study, the anti-metastatic potential of the methanol extract of Solanum muricatum (S. muricatum) was evaluated using B16F-10 melanoma cell-induced lung metastasis in C57BL/6 mice. Treatment with S. muricatum significantly inhibited the lung tumor nodule formation and reduced the lung collagen hydroxyproline, hexosamine, and uronic acid levels (p<0.01). Similarly, serum sialic acid and γ-glutamyl transpeptidase levels were also significantly inhibited after S. muricatum treatment. The levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, granulocyte monocyte colony-stimulating factor (GM-CSF), and IL-2 in serum were significantly regulated after treatment with S. muricatum. The serum nitric oxide level was also decreased significantly and was accompanied by a decrease in inducible nitric oxide synthase (iNOS) and cyclo- oxygenase (COX)-2 expressions after S. muricatum treatment. The present study reveals that S. muricatum treatment was able to alter the proinflammatory cytokine production as well as inhibit the activation and nuclear translocation of nuclear factor-κB (p65 and p50) subunits.

Cuscuta chinensis Ameliorates Immunosuppression and Urotoxic Effect of Cyclophosphamide by Regulating Cytokines - GM-CSF and TNF-Alpha.

Cancer is the leading cause of death worldwide. Cyclophosphamide (CTX) is commonly used as anticancer drug which causes toxicity by its reactive metabolites such as acroline and phosphoramide mustard. In this study, Cuscuta chinensis (C. chinensis) (family: Convolvulaceae) was assessed for ability to restore mice against CTX-induced toxicity. Coadministration of C. chinensis extract (10 mg/kg BW, IP, daily) for ten consecutive days reduced CTX-induced (25 mg/kg BW, IP, daily) toxicity. Treatment with C. chinensis extract significantly (p < 0.01) increased the relative organ weight and body weight. Moreover, administration of C. chinensis extract significantly increased bone marrow cellulatity and α-esterase activity in CTX-treated mice which suggested its protective role on the hematopoietic system. The GSH content was drastically reduced by CTX administration in urinary bladder which was enhanced by treatment with C. chinensis extract, indicating that preventing acroline-mediated tissue damage or cell toxicity and also the extract decreased the urinary bladder nitric oxide (NO) level which proves recovery over urinary tract injury associated with CTX treatment. The administration of C. chinensis extract decreased serum urea, creatinine, and bilirubin levels when compared to CTX-alone-treated group. Histopathological analysis of the urinary bladder of CTX-alone-treated group showed necrotic damage whereas the C. chinensis-treated group showed normal bladder architecture. The above data clearly demonstrates chemoprotective role of C. chinensis against CTX-induced toxicities by regulating antioxidant and inflammatory mediators.

Anti-tumor and Chemoprotective Effect of Bauhinia tomentosa by Regulating Growth Factors and Inflammatory Mediators.

Cancer is a leading cause of death worldwide. Due to the toxic side effects of the commonly used chemotherapeutic drug cyclophosphamide (CTX), the use of herbal medicines with fewer side effects but having potential use as inducing anti-cancer outcomes in situ has become increasingly popular. The present study sought to investigate the effects of a methanolic extract of Bauhinia tomentosa against Dalton's ascites lymphoma (DAL) induced ascites as well as solid tumors in BALB/c mice. Specifically, B. tomentosa extract was administered intraperitonealy (IP) at 10 mg/kg. BW body weight starting just after tumor cell implantation and thereafter for 10 consecutive days. In the ascites tumor model hosts, administration of extract resulted in a 52% increase in the life span. In solid tumor models, co-administration of extract and CTX significantly reduced tumor volume (relative to in untreated hosts) by 73% compared to just by 52% when the extract alone was provided. Co-administration of the extract also mitigated CTX-induced toxicity, including decreases in WBC count, and in bone marrow cellularity and α-esterase activity. Extract treatment also attenuated any increases in serum levels of TNFα, iNOS, IL-1ß, IL-6, GM-CSF, and VEGF seen in tumor-bearing hosts. This study confirmed that, the potent antitumor activity of B.tomentosa extract may be associated with immune modulatory effects by regulating anti-oxidants and cytokine levels.

Acacia ferruginea inhibits cyclophosphamide-induced immunosuppression and urotoxicity by modulating cytokines in mice.

Cyclophosphamide (CTX), commonly used as an anti-neoplastic drug, can cause adverse side-effects including immunotoxicity and urotoxicity. Increasingly, plants have become sources of therapeutics that can help to restore host immunity to normal. In this study, Acacia ferruginea was assessed for an ability to protect mice against/mitigate CTX-induced toxicity. Co-administration of an extract of A. ferruginea (10 mg/kg BW, IP daily) for 10 consecutive days reduced CTX (25 mg/kg BW, IP daily)-induced toxicity. Apart from improvements in bladder and small intestine morphology, there was marked improvement in anti-oxidant (glutathione) levels in the bladder, suggesting a role for the anti-oxidant in reducing CTX-induced urotoxicity. Moreover, use of the extract significantly increased total leukocyte counts and bone marrow cellularity/α-esterase activity in CTX-treated mice which suggested a protective effect on the hematopoietic system. Co-treatment with the extract also prevented decreases in organ (liver, kidney, spleen, thymus) weight as well as body weight, thereby seemingly lessening the potential impact of CTX on the host immune system. Further, CTX-induced increases in serum aspartate transanimase, alanine transaminase, and alkaline phosphatase were reversed by extract co-treatment, as were alterations in in situ formation/release of interferon (IFN)-γ, interleukin (IL)-2, granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α. Overall, this study indicated there were some protective effects from use of an extract of A. ferruginea against CTX-induced toxicities, in part through modulation of levels of anti-oxidants and pro-inflammatory cytokines.

Solanum muricatum Ait. inhibits inflammation and cancer by modulating the immune system.

CONTEXT: The pepino fruit Solanum muricatum Ait. (Solanaceae) is commonly known as melon pear and sweet cucumber grown in South America, New Zealand, and India. Traditionally, the fruits are used in the treatment of diabetes and cancer. AIM: The objective of present study is to explore the immunomodulatory, anticancer, and anti-inflammatory activities of the methanol extract of S. muricatum fruits in experimental mice models. MATERIALS AND METHODS: Immunomodulatory activity of S. muricatum fruits was evaluated by assessing the relative organ weight, bone marrow cellularity, α-esterase activity, and by studying the phagocytic activity by carbon clearance test. The anti-tumor activity of the fruit extract was studied against Dalton's lymphoma ascites (DLA) cell line induced solid and ascites tumor models. The anti-inflammatory activity of the fruit extract was evaluated using carrageenan and formaldehyde models. STATISTICAL ANALYSIS: The results were expressed as mean (±SD). Statistical analyses were performed using a one-way analysis of variance (ANOVA) followed by Dunnett's test using GraphPad Instat software. P values less than 0.05 were considered statistically significant. RESULTS: S. muricatum treatment could not only stimulate the immune system but also significantly (P < 0.01) inhibit the growth of transplantable tumor. The serum glutathione and γ-glutamyl transpeptidase (GGT) levels were found to be significantly decreased compared with tumor-bearing control animals. The increased tumor necrosis factor (TNF)-α level in tumor control (802.6 ± 12.0) was significantly (P < 0.01) decreased to 175.2 ± 16.5 after S. muricatum treatment. The TNF-α level in normal animals was found to be 21.0 ± 3.5 pg/ml. An increase in life span was observed after S. muricatum treatment. The extract also inhibited the edema induced by carrageenan and formaldehyde, respectively. CONCLUSION: The results showed that the S. muricatum fruit extract has potent immunomodulatory, anticancer, and anti-inflammatory activities.

Protective effect of Acacia ferruginea against ulcerative colitis via modulating inflammatory mediators, cytokine profile and NF-κB signal transduction pathways.

In the present study, we evaluated the protective effect of A. ferruginea extract against ulcerative colitis (UC). Male Wistar rats received A. ferruginea extract (10 mg/kg body weight) or sulfasalazine (100 mg/kg body weight) for 5 consecutive days before inducing UC via intrarectal acetic acid (3%) administration. Colonic mucosal injury was assessed by macroscopic scoring, vascular permeability testing, and histopathological examination. The mucosal contents of glutathione, lipid peroxidation, superoxide dismutase, and nitric oxide were evaluated as parameters for the redox state. Inflammatory response was determined by measuring inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) expression. Myeloperoxidase (MPO), lactate dehydrogenase assay (LDH), tumor necrosis factor (TNF-α), and interleukins (IL-1ß and IL-6) were measured using ELISA. Transcription factor profiling of nuclear factor (NF)-κB subunits (p65/p50) was also conducted using ELISA. All of the relevant parameters were altered in rats with UC, and these parameters improved in animals that received A. ferruginea extract. Colonic mucosal injury parallels antioxidant and anti-inflammatory evaluations, and A. ferruginea extract was considered comparable to the standard treatment drug sulfasalazine. Histopathological studies confirmed these findings. A. ferruginea extract inhibited the activation and translocation of transcription factors, that is, NF-κB subunits (p65/p50). The results of our investigation clearly indicate that treatment with A. ferruginea extract exerted a marked protective effect against experimental UC via modulation of oxidant/anti-oxidant balance and inhibition of inflammatory mediators.

Protective Effect of Acacia nilotica (L.) against Acetaminophen-Induced Hepatocellular Damage in Wistar Rats.

The potential biological functions of A. nilotica have long been described in traditional system of medicine. However, the protective effect of A. nilotica on acetaminophen-induced hepatotoxicity is still unknown. The present study attempted to investigate the protective effect of A. nilotica against acetaminophen-induced hepatic damage in Wistar rats. The biochemical liver functional tests Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALP), total bilirubin, total protein, oxidative stress test (Lipid peroxidation), antioxidant parameter glutathione (GSH), and histopathological changes were examined. Our results show that the pretreatment with A. nilotica (250 mg/kg·bw) orally revealed attenuation of serum activities of ALT, AST, ALP, liver weight, and total bilirubin levels that were enhanced by administration of acetaminophen. Further, pretreatment with extract elevated the total protein and GSH level and decreased the level of LPO. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by acetaminophen. The present study undoubtedly provides a proof that hepatoprotective action of A. nilotica extract may rely on its effect on reducing the oxidative stress in acetaminophen-induced hepatic damage in rat model.

Acacia ferruginea inhibits tumor progression by regulating inflammatory mediators-(TNF-a, iNOS, COX-2, IL-1ß, IL-6, IFN-γ, IL-2, GM-CSF) and pro-angiogenic growth factor- VEGF.

The aim of the present investigation was to evaluate the effect of A ferruginea extract on Dalton's lymphoma ascites (DLA) induced tumours in BALB/c mice. Experimental animals received A ferruginea extract (10 mg/ kg.b.wt) intraperitoneally for 14 consecutive days after DLA tumor challenge. Treatment with extract significantly increased the life span, total white blood cell (WBC) count and haemoglobin (Hb) content and decreased the level of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (γ-GT) and nitric oxide (NO) in DLA bearing ascites tumor models. In addition, administration of extract significantly decreased the tumour volume and body weight in a DLA bearing solid tumor model. The levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and granulocyte monocyte-colony stimulating factor (GM-CSF), as well as pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) were elevated in solid tumour controls, but significantly reduced by A ferruginea administration. On the other hand, the extract stimulated the production of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in animals with DLA induced solid tumours. Increase in CD4+ T-cell population suggested strong immunostimulant activity for this extract. GC/MS and LC/MS analysis showed quinone, quinoline, imidazolidine, pyrrolidine, cyclopentenone, thiazole, pyrazole, catechin and coumarin derivatives as major compounds present in the A ferruginea methanolic extract. Thus, the outcome of the present study suggests that A ferruginea extract has immunomodulatory and tumor inhibitory activities and has the potential to be developed as a natural anticancer agent.

The effect of Thespesia populnea on cisplatin induced nephrotoxicity.

AIM OF THE STUDY: To study the effect of Thespesia populnea on Cisplatin induced Nephrotoxicity. MATERIALS AND METHODS: Experiments were conducted on Male Sprague Dawley Rats (4-6 weeks old) weighing 100-120g B.Wt. The drug under study was cisplatin, which is an anticancer drug. Thespesia populnea extract was used to test its ability to alleviate the harmful effects of cisplatin. The animals were divided into three groups: Group I was considered as normal, Group II was given a single dose of cisplatin (6 mg/kg/b.wt., i.p) and they constituted the control animals and Group III was treated with cisplatin along with Thespesia populnea (5 mg/kg/b.wt., i.p) for 10 consecutive days. RESULTS: Administration of cisplatin resulted in significant (P < 0.05) increase in the levels of serum urea (137 ± 1.6), creatinine (1.69 ± 0.14), ALT (96.18 ± 3.44), AST (80.84 ± 3.34) and bilirubin (4.57 ± 0.08) as compared to normal animals. On the other hand, introduction of Thespesia populnea extract caused a significant (P < 0.05) reduction in the levels of serum markers namely urea (112 ± 2.16), creatinine (0.54 ± 0.004), ALT (76.4 ± 1.45), AST (58.80 ± 1.6) and bilirubin (3.96 ± 0.85). DISCUSSION: Increase in the levels of urea and creatinine in serum as well as ALT, AST and bilirubin is suggestive of both kidney and liver damage. Thespesia populnea extract ameliorated cisplatin induced kidney and liver damage as indicated by reduction in the levels of serum urea, creatinine, AST, ALT and bilirubin. Reduction in the levels of these biochemical markers is an indication of regeneration process. Thus it is concluded that the extract might contain nephroprotective compounds such as flavonoids, alkaloids, etc. which are responsible for alleviating cisplatin induced toxicity.

Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice.

Amentoflavone has been shown to inhibit tumor metastasis in vivo, but its mechanism of action remains unclear. Here, C57BL/6 mice were injected once with B16F-10 melanoma cells via tail vein followed by amentoflavone treatment (50 mg/kg BW) for 10 consecutive days. Twenty-one days after tumor injection, animals were euthanized, and tumor metastasis was found to confine in the lungs. As compared with the tumor controls, amentoflavone treatment significantly lowered the number of lung nodules (p<0.001). Amentoflavone treatment markedly decreased the mRNA expression of MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, TNF-alpha, IL-1beta, IL-6, and GM-CSF in lung tissues. However, amentoflavone treatment increased the mRNA expression of STAT-1 and nm23 in lung tissues. Also in vitro studies indicate that amentoflavone treatment inhibits tumor cell invasion and migration. These results show that amentoflavone treatment reduces experimental tumor metastasis and suggest that such an action is associated with attenuation of tumor invasion, proliferation and angiogenesis.