Antimetastatic Activity Research Articles

New fluorobenzamidine exerts antitumor activity against breast cancer in mice via pro-apoptotic activity

BackgroundBreast cancer is one of the leading causes of cancer-related morbidities. The present study aimed to evaluate the efficacy of bithiophene-fluorobenzamidine (BFB) against breast cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) in female Swiss mice and reveal the underlining mechanisms.MethodsThe mice were randomly divided into five groups; control, BFB-treated group, DMBA-treated group, and the last two groups received DMBA then tamoxifen or BFB.ResultsBFB reduced the tumor incidence by ~ 88% versus 30% after TAM. DMBA significantly increased the expression of CDK1 and HER2 and reduced the expression of p53, p21 (CDKN1A), ESR-α, and CAS3. BFB caused significant down-regulation of CDK1 and HER2 and upregulation of p53, p21, ESR-α, and CAS3. In the DMBA-treated mice, cancerous cells metastasized to several organs. This was prevented by the administration of BFB. The antimetastatic and proapoptotic activities were confirmed in MCF7 cells in vitro by the wound healing and annexin V assays, respectively. Kaplan–Meier analysis showed that the BFB increased survival. In the DMBA group, tumors showed invasive carcinoma of grade III with central necrosis, polymorphism, mitotic activity, and numerous newly formed ductules, and colloidal mucinous secretions within adenoid cysts. BFB administration restored the normal structure of the mammary glands.ConclusionTaken together, BFB has antitumor, pro-apoptotic, and anti-metastatic activities against breast cancer in mice and therefore, it merits further investigations.

Antitumor activity of the novel pyridine derivative

Introduction: The study aim was to explore a toxicological property and antitumor action of the novel pyridine deriv­ative LHT-17-19 in cell culture and on experimental models of lung cancer in mice.
 Materials and methods: The study was performed on male and female ICR(CD-1), male BALB/c, male BALB/c nu/nu mice. Pyridine derivative (LHT-17-19) was studied as water-soluble pharmaceutical substance. Acute toxicity was evaluated in groups of 5 animals, and the results were analyzed by Finney. Antitumor and antimetastatic activity was studied in syngeneic and xenograft models of lung cancer in mice.
 Results and discussion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with GOST 12.1.007–76. The substance demonstrated an antitumor and antimetastatic property in mice with syngeneic tumor Lewis lung carcinoma as well as on the heterotopic tumor model of non-small cell lung cancer in humanized animals.
 Conclusion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with WHO recom­mendation. LHT-17-19 exerts antitumor and antimetastatic property on both syngeneic and patient-derived lung cancer xenograft murine models.
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Resveratrol reverses TGF-β1-mediated invasion and metastasis of breast cancer cells via the SIRT3/AMPK/autophagy signal axis.

Resveratrol (Resv) has antitumorigenic and antimetastatic activities; however, the molecular mechanisms underlying the inhibitory effects of Resv on the invasion and metastasis of breast cancer cells are still a subject of debate. In our study, we demonstrated that Resv inhibited tumor cell proliferation and tumor growth. It also suppressed invasion and pulmonary metastasis of breast cancer by reversing the transforming growth factor beta 1 (TGF-β1)-mediated EMT process. Meanwhile, the anticarcinogenic effects of Resv were abolished by the autophagy blocker 3-methyladenine (3-MA) or Beclin 1 small interfering RNA. Moreover, Resv upregulated autophagy-related genes and protein levels and induced the formation of autophagosomes in 4T1 breast cancer cells and xenograft mice, suggesting that autophagy was involved in the anticarcinogenic activities of Resv in both models. In addition, Resv-induced autophagy by increasing the expression of SIRT3 and phosphorylated AMPK. SIRT3 knockdown reduced AMPK phosphorylation and autophagy-related proteins levels, and suppressed the anticancer effects of Resv, demonstrating that the inhibitory effects of Resv on tumor progression were mediated via the SIRT3/AMPK/autophagy pathway. Taken together, our study provided novel insight into the anticancer effects of Resv and revealed that targeting the SIRT3/AMPK/autophagy pathway can serve as a new therapeutic target against breast cancer.

Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

The present work provided in vitro anticancer investigation of novel spirooxindole based benzimidazole scaffold SP1 and its nanoformulation with in vivo evaluation of anticancer and antimetastatic activity as potential drug for breast adenocarcinoma. The synthesized compound SP1 exhibited potent growth inhibitory efficacy against four types of human cancer (breast, prostate, colon and lung) cell lines with IC50 = 2.4, 3.4, 7.24 and 7.81 µM and selectivity index 5.79, 4.08, 1.93 and 1.78 respectively. Flow cytometric analysis illustrated that SP1 exhibited high apoptotic effect on all tested cancer cell lines (38.22–52.3 %). The mode of action of this promising compound was declared by its ability to upregulate the gene expression of p21 (2.29–3.91 folds) with suppressing cyclin D (1.9–8.93 folds) and NF-κB (1.26–1.44 fold) in the treated cancer cells. Also, it enhanced the protein expression of apoptotic marker p53 and moderate binding affinity for MDM2 (KD;7.94 μM). Notwithstanding these promising impressive findings, its selectivity against cancer cell lines and safety on normal cells were improved by nanoformulation. Therefore, SP1 was formulated as ultra-flexible niosomal nanovesicles (transethoniosomes). The ultra-deformability is attributable to the synergism between ethanol and edge activators in improving the flexibility of the nanovesicular membrane. F8 exhibited high deformability index (DI) of (23.48 ± 1.4). It was found that % SP1 released from the optimized transethoniosomal formula (F8) after 12 h (Q12h) was 84.17 ± 1.29 % and its entrapment efficiency (%EE) was 76.48 ± 1.44 %. Based upon the very encouraging and promising in vitro results, an in vivo study was carried out in female Balb/c mice weighing (15–25 g). SP1 did halt the proliferation of breast cancer cells as well as suppressed the metastasis in other organs like liver, lung and heart.

In Vitro anti-metastasis of Perilla frutescens leaf water extract on aggressive human breast cancer cells

Background: Perilla frutescens is a long-established plant that is often used in foods and traditional medicines in Asian countries. The perilla leaf contains a considerable number of bioactive substances, such as phenolics and flavonoids, which have been demonstrated to possess anticancer activity in vitro and in vivo. Objectives: We aimed to study anti-metastatic activity, anti-invasion activity, and anti-migration activity of perilla leaf water extract (PLW) at 90°C for 1-5 min in MDA-MB-231 aggressive human breast cancer cells. Materials and methods:Dry perilla leaves were extracted using hot water for 1-5 min to obtain crude extract and then lyophilized for PLW powder. PLW was evaluated for total phenolic, total flavonoid, and rosmarinic acid (RA) contents by Folin-Ciocalteau reagent, aluminum chloride colorimetric assay, and ultra-high-pressure liquid chromatography, respectively. Antioxidant activity of PLW was determined by DPPH and ABTS assays. MTT assay was performed to evaluate the cytotoxicity of PLW on MDA-MB-231 cells. Effective PLW was further determined its inhibitory effect on human breast cancer cell metastasis by a Boyden chamber-based transmembrane assay, the MMP-9 activity, and the proteolytic type IV collagenase activity. Results: PLW by 5-min infusion showed the highest amount of total phenolic and flavonoid contents, as well as RA. Moreover, by the 5-min infusion, PLW had the highest antioxidant capacity when compared to PLW by infusions for 1-4 min. Following that, cytotoxicity testing revealed that the PLW is not toxic to MDA-MB-231 cells after a 24-hr exposure. The PLW at non-toxic doses (12.5-100 µg/mL) intensely presents an inhibitory effect on cell invasion and migration. The gelatinolytic activity showed that the PLW at concentrations of 12.5-100 µg/mL decreases MMP-9 activity in a dose-related manner. Furthermore, after treatment with the PLW, the proteolytic type IV collagenase activity was reduced considerably in a dose-related manner. Conclusion: Our findings further showed that the PLW samples inhibit proteolytic enzymes involved in basement membrane breakdown, which might explain the anti-invasion and anti-migration properties of breast cancer cells. From the result, the application of perilla leaf might be developed as an herbal tea and used as an anti-metastatic agent for breast cancer prevention and treatment.

Phenylpropenol ester and sesquiterpenoids with antimetastatic activities from the whole plants of Chloranthus japonicus

One new phenylpropenol ester (1) and three new lindenane sesquiterpenes (2–4) were isolated from the whole plant of Chloranthus japonicus together with three known lindenane derivatives (5–7). Their structures were determined based on detailed spectroscopic and electronic circular dichroism computational analyses. Compound 4 showed moderate efficacy in inhibiting cell migration, invasion, and vasculogenic mimicry (VM) in human of hepatocarcinoma (HCC) HepG2 cells. Furthermore, compound 4 could alter the expression of the proteins Vimentin, N-cadherin, Snail1 and E-cadherin by down-regulating the expression of Twist1, which indicated that its antimetastatic effect was associated with restraining the epithelial-mesenchymal transition (EMT) in HepG2 cells.

Comparative Analysis of the Pharmacological Activity of Bis(3,5-di-Tert-Butyl-4-Hydroxyphenylthiolate)Dimethylol in Different Modes of Administration on a Mouse Model of Melanoma B16 Tumor Growth.

We performed a comparative analysis of the pharmacological activity of the hybrid organotin compound bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) administered in different modes to mice with transplanted melanoma B16 to identify the most effective dosage regimen. Three modes of administration were used: preventive (before transplantation of tumor cells), classical according to Z. P. Sof'ina (48 h after transplantation of tumor cells), and delayed (7 days after transplantation of tumor cells, after formation of nodules of the primary tumor node). Compound Me-3 was administered at a total dose of 375 mg/kg intraperitoneally once a day for 5 days. The classical mode of administration was identified as the most effective, which indicates the preventive antimetastatic activity of Me-3 on the model of the transplanted mouse tumor melanoma B16.

The Regulators of Peroxisomal Acyl-Carnitine Shuttle CROT and CRAT Promote Metastasis in Melanoma

Circulating tumor cells (CTCs) are the key link between a primary tumor and distant metastases, but once in the bloodstream loss of adhesion induces cell death. To identify mechanisms relevant for melanoma CTC survival we performed RNAseq and discovered that detached melanoma cells and isolated melanoma CTCs rewire lipid metabolism by up-regulating fatty acid transport and fatty acid beta-oxidation (FAO) related genes. In melanoma patients high expression of fatty acid transporters and FAO enzymes significantly correlates with reduced progression free and overall survival. Amongst the highest expressed regulators in melanoma CTCs were the carnitine-transferases CROT and CRAT, which control the shuttle of peroxisome derived medium-chain fatty acids (MCFAs) towards mitochondria to fuel mitochondrial FAO. Knockdown of CROT or CRAT and short-term treatment with peroxisomal or mitochondrial FAO inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. CROT and CRAT depletion could be rescued by MCFA supplementation, indicating that the peroxisomal supply of fatty acids is crucial for the survival of non-adherent melanoma cells. Our study identifies targeting the fatty acid based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the anti-metastatic activity of the FDA-approved drug ranolazine carries translational potential.

Evaluation of anticancer activity of ferrocene based benzothiazole and β-ketooxothioacetal

Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity.

Modified Bu-Fei decoction inhibits lung metastasis via suppressing angiopoietin-like 4

BackgroundModified Bu-Fei decoction (MBFD), a formula of traditional Chinese medicine, is used for treating lung cancer in clinic. The actions and mechanisms of MBFD on modulating lung microenvironment is not clear. PurposeLung microenvironment is rich in vascular endothelial cells (ECs). This study is aimed to examine the actions of MBFD on tumor biology, and to uncover the underlying mechanisms by focusing on pulmonary ECs. MethodsThe Lewis lung carcinoma (LLC) xenograft model and the metastatic cancer model were used to determine the efficacy of MBFD on inhibiting tumor growth and metastasis. Flow cytometry and trans-well analysis were used to determine the role of ECs in anti-metastatic actions of MBFD. The in silico analysis and function assays were used to identify the mechanisms of MBFD in retarding lung metastasis. Plasma from lung cancer patients were used to verify the effects of MBFD on angiogenin-like protein 4 (ANGPTL4) in clinical conditions. ResultsMBFD significantly suppressed spontaneous lung metastasis of LLC tumors, but not tumor growth, at clinically relevant concentrations. The anti-metastatic effects of MBFD were verified in metastatic cancer models created by intravenous injection of LLC or 4T1 cells. MBFD inhibited lung infiltration of circulating tumor cells, without reducing tumor cell proliferations in lung. In vitro, MBFD dose-dependently inhibited trans-endothelial migrations of tumor cells. RNA-seq assay and verification experiments confirmed that MBFD potently depressed endothelial ANGPTL4 which is able to broke endothelial barrier and protect tumor cells from anoikis. Database analysis revealed that high ANGPTL4 levels is negatively correlated with overall survival of cancer patients. Importantly, MBFD therapy reduced plasma levels of ANGPTL4 in lung cancer patients. Finally, MBFD was revealed to inhibit ANGPTL4 expressions in a hypoxia inducible factor-1α (HIF-1α)-dependent manner, based on results from specific signaling inhibitors and network pharmacology analysis. ConclusionMBFD, at clinically relevant concentrations, inhibits cancer lung metastasis via suppressing endothelial ANGPTL4. These results revealed novel effects and mechanisms of MBFD in treating cancer, and have a significant clinical implication of MBFD therapy in combating metastasis.

N-acetyl-galactosamine modified metal-organic frameworks to inhibit the growth and pulmonary metastasis of liver cancer stem cells through targeted chemotherapy and starvation therapy

Hepatocellular carcinoma (HCC) is a common high-mortality malignancy which still needs efficient treatments. HCC patients undergoing extrahepatic metastases are mostly with unsatisfactory prognosis. Therefore, specific attention has been paid to extrahepatic HCC metastasis. We integrated Sorafenib (Sor) and glucose oxidase (GOx) into a N-acetyl-galactosamine (GalNAc) modified zeolitic imidazolate framework (ZIF-8), designated as SG@GR-ZIF-8, for targeted bimodal therapies of chemotherapy and starvation therapy against HCC. The hepatic delivery of SG@GR-ZIF was mediated by the specific recognition of GalNAc residues with asialoglycoprotein (ASGPR) on the liver cell surface. Sor is a clinically approved anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. GOx can efficiently induce cell death and disturb malignant progression by suppressing glucose supply of cancer cells, which is highly associated with metabolic rewiring in metastasis. The nano-formulation exhibit significant anti-metastatic HCC activity against C5WN1 cells, a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In a subcutaneous C5WN1-tumor carrying mouse model, SG@GR-ZIF exhibits potent synergistic anti-tumor activity with a tumor inhibition rate of 89% and a prolonged survival status. The growth and pulmonary metastasis of HCC in an orthotopic mouse model of HCC was remarkably suppressed in SG@GR-ZIF treated group. The therapeutic strategy targeting energy supply combined with first-line treatment holds great promise for the future treatment of metastatic HCC. Statement of significanceSG@GR-ZIF, a N-acetyl-galactosamine modified metal-organic framework carrying Sorafenib and glucose oxidase, was fabricated for treating metastatic hepatocellular carcinoma (HCC). Sorafenib is an anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. Glucose oxidase blocks energy demand in HCC metastasis by depleting glucose. C5WN1 was used for therapeutic evaluations as a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In subcutaneous C5WN1-tumor bearing mice, SG@GR-ZIF exhibited a tumor inhibition rate of 89% and prolonged survival period. In orthotopic C5WN1-tumor carrying mice, the growth and pulmonary metastasis of hepatocarcinoma was remarkably suppressed by SG@GR-ZIF. Together, this study suggests the great potential of synergistic chemo/starvation therapy mediated by SG@GR-ZIF for treating metastatic HCC.

The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines.

The present study aimed to investigate in-depth a cytotoxic novel benzofuran-isatin conjugate (5a, 3-methyl-N'-(2-oxoindolin-3-ylidene)benzofuran-2-carbohydrazide) with promising potential anticancer activities in colorectal adenocarcinoma HT29 and metastatic colorectal cancer (CRC) SW620 cell lines. Thus, the primary cell events involved in tumorigenicity, tumor development, metastasis, and chemotherapy response were explored. Both CRC cell lines were exposed to different concentrations of Compound 5a and then subjected to real-time cell viability, migration, and invasion assays, colony formation and cytotoxicity assays, and flow cytometry for cell cycle analysis and apoptosis determination. Western blot and RT-qPCR were performed to assess the protein and transcript expression levels of epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis markers. We showed that the Compound 5a treatment exhibited anticancer effects through inhibition of HT29 and SW620 cell viability, migration, and invasion, in a dose-dependent manner, which were associated with the upregulation of the tumor suppressor p53. Compound 5a also inhibited the colony formation ability of HT29 and SW620 cells and reversed EMT markers E-cadherin and N-cadherin expression. CRC cell exposure to Compound 5a resulted in a cell cycle arrest at the G1/G0 phase in HT29 cells and at the G2/M phase in SW620 cells, along with the downregulation of cyclin A1 expression, described to be involved in the S phase entry. Furthermore, Compound 5a-induced apoptosis was associated with the downregulation of the anti-apoptotic Bcl-xl marker, upregulation of pro-apoptotic Bax and cytochrome c markers, and increased mitochondrial outer membrane permeability, suggesting the involvement of mitochondria-dependent apoptosis pathway. In addition, the combination studies of Compound 5a with the main conventional chemotherapeutic drugs 5-fluorouracil, irinotecan, and oxaliplatin showed a more potent cytotoxic effect in both CRC cells than a single treatment. In conclusion, our findings described the interesting in vitro anticancer properties of Compound 5a, shown to have possible antitumor, antimetastatic, and pro-apoptotic activities, with the enhancement of the cytotoxic efficiency of conventional chemotherapeutic drugs. In vivo studies are requested to confirm the promising anticancer potential of Compound 5a for CRC therapy.

Functional profiling of Achillea fragrantissima (a perennial edible herb) against human cancer cells and potential nutraceutical impact in neutralizing cell proliferation by interfering with VEGF and NF-κB signaling pathways

Chemoprevention with alternative approaches is emerging as a significant component of therapeutic regimen for the management of various diseases in human population including cancer. The concept of personalized nutrition is attracting considerable interest as an effective and affordable strategy in the prevention of chronic diseases. It is acknowledged that diet-derived agents or non-dietary natural products are not only the source of traditional medicines but also the lead compounds for currently used pharmaceuticals with excellent efficacy against a number of human diseases. Achillea species (Asteraceae) are considered as functional foods, which are important constituents of traditional medicine and commonly consumed as herbal tea or food additives worldwide. The studies presented herein demonstrate the effects of the hydro-methanolic extract of A. fragrantissima against a panel of cancer cells that include breast cancer (MDA-MB-231,MCF-7,SKBR3), pancreatic cancer (BxPC-3, MiaPaCa-2), prostate cancer (LNCaP,C4-2B,PC-3), and lung cancer (A549). The experimental results presented in the study show that the extract, which is rich in structurally diverse phytochemicals, effectively inhibits the cell growth and induces apoptotic cell death in human cancer cells. The treatment of the cancer cells with the extract resulted in a progressive decrease in cell migration and invasiveness, demonstrating an effective anti-metastatic activity. The mechanism by which the extract exerts its effects against cancer cells potentially engages NF-κB signaling and downregulation of its target cytokines such as VEGF. The study provides evidence that partially support the importance of functional foods and highlights their significance in disease prevention.

How do phenolic compounds act in the prevention and treatment of cancer?

Cancer is the transformation of healthy cells into tumor cells in a multistage process that can affect any organ of the body. This disease is the second leading cause of death globally. There are now more than 10 million cancer cases per year worldwide, and the most common occurs in the lung, breast, and colon. Several studies demonstrate that lifestyle and eating habits are directly related to tumor cells’ appearance, such as high body mass index, low fruit and vegetable intake, lack of physical activity, and tobacco and alcohol use. It is widely believed that diet and nutrients can act as cancer risk-modifiers throughout the process of carcinogenesis, including initiation, promotion, progression, and/or conversion. Different plants have been the source of therapeutic agents. Plant-derived compounds have become indispensable for modern pharmacotherapy, and phenolic compounds are one of the most investigated due to their antitumor activity. Their cellular targets and mechanisms are compiled in the present work. Phenolic compounds are secondary metabolites present in large quantities in medicinal herbs and dietary plants (e.g., fruits, vegetables, and spices). They possess a diverse range of beneficial biological activities, which contribute to their potent effects on inhibiting carcinogenesis. Some benefits include cell proliferation and angiogenesis inhibition and anti-inflammatory, antioxidant, and antimetastatic activities. Thus, the present review supports the recommendations for consuming foods and drinks rich in phenolic compounds to prevent and possibly treat cancer.

Tumor inhibitory effect via immunostimulating activities of a rhamnogalacturonan-I-rich polysaccharide isolated from turmeric (Curcuma longa L.).

In this study, a turmeric polysaccharide (TP-0) was isolated through hot water extraction and ethanol precipitation to produce a novel active polysaccharide from turmeric other than curcuminoids. TP-0 was found to be primarily composed of eight different monosaccharides, such as galactose (15.9%), galacturonic acid (15.2%), arabinose (11.4%), and rhamnose (9.7%), which are typical rhamnogalacturonan (RG)-I sugars. When stimulated with TP-0, peritoneal macrophages secreted a variety of immunostimulatory cytokines. In addition, intravenous and oral administration of TP-0 significantly enhanced the natural killer (NK) cells and cytotoxic T lymphocyte (CTL)-mediated cytotoxicity against tumor cells. In an assay for lung cancer induced by Colon26-M3.1 carcinoma, prophylactic intravenous and oral administration of TP-0 effectively inhibited lung cancer. These findings reveal that TP-0, a typical RG-I-type polysaccharide that is isolated from turmeric, has potent anti-metastatic activities, and these activities are linked to various immunological factors such as macrophages, NK cells, and CTL. PRACTICAL APPLICATIONS: Many studies related with turmeric have only focused that a curcuminoid of turmeric has beneficial effects on human health system. Nevertheless, in this study, it was confirmed that polysaccharide isolated from turmeric showed potent anti-cancer effects via activities of various immunological factors such as macrophages, NK cells, and CTL. These results suggest the high potential for development value of turmeric as a new candidate for immunostimulating-related health functional food ingredients.

β-Eudesmol Inhibits the Migration of Cholangiocarcinoma Cells by Suppressing Epithelial-Mesenchymal Transition via PI3K/AKT and p38MAPK Modulation.

Cholangiocarcinoma (CCA) is a highly aggressive tumor with a greater risk of distant metastasis. A drug that prevents CCA development and spread is urgently needed. In this research, we investigated the effect of β-eudesmol on the migration and invasion and epithelial-mesenchymal transformation (EMT) of the CCA cell line. MTT and transwell assays were used to investigate the antiproliferative activity, as well as activity on cell migration and cell invasion. Real-time PCR and western blot analysis were used to investigate the expression of EMT marker genes and proteins. β-eudesmol was shown to exhibit potent antiproliferative activity (IC50 92.25-185.67 µM) and to significantly reduce CCA cell migration and invasion (27.3-62.7%). At both mRNA and protein levels, it significantly up-regulated the expression of epithelial marker E-cadherin (3-3.4-fold), while down-regulated the expression of mesenchymal markers-vimentin (0.6-0.8-fold) and snail-1 (0.4-0.6-fold). Furthermore, β-eudesmol inhibited PI3K and AKT phosphorylation (0.5-0.8-fold), while activating p38MAPK activity (1.2-3.6-fold). Altogether, the anti-metastatic activity of β-eudesmol might be due to its suppressive effect on EMT via modulating the PI3K/AKT and p38MAPK signaling cascades.

Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and immunofluorescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung-intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro-inflammatory cytokine interleukin-1β, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast-specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.

Review on Anticancer properties of Piperine in Oral cancer: Therapeutic Perspectives

Cancer is a one of the leading causes of death in the world, continue to be worldwide eradicator. Multi-drug resistance (MDR) is a major problem with the current treatment options. It is now widely believed that many herbal dietary products are available as chemoprotective agents against commonly occurring cancer types. Piperine is an alkaloid; exhibit a wide spectrum of biological and pharmacological activities like anti-pyretic, antimetastatic, antidepressant, antiapoptotic and antitumor activity. In this review, to focus effect of piperine on anticancer research related to their mechanism of action and its ability to regulate cancer related gene action like oncogenic and tumour supprosser gene in cycle and apoptosis as well as its therapeutic perspectives on oral cancer, online-literature were studied which includes books on phytochemistry and the electronic search (SciFinder, Pubmed, the Web of Science, Scopus, Google Scholar and etc). Piperine action on apoptosis pathway via caspases signalling has been studied in many researches, in which piperine disrupts cell proliferation and induces apoptosis. Piperine had the ability to cause cell cycle arrest in G2/M phase and to activate caspase-3 and caspase-9 cascades showed selective cytotoxicity and also through the downregulation of cyclin B1 and enhanced phosphorylation of cyclin-dependent kinase-1 (CDK1) and check point kinase 2 in cell cycle. It also inhibits the functions of P-glycoprotein (P-gp) and CYP3A4, which not only affects drug metabolism but also re-sensitizes multidrug resistant (MDR) cancer cells. Anti-proliferative and pro-apoptotic nature of Piperine extends its activity by stabilizing the G-quadruplex structure formed at c-myc promoter region and down regulating its expression in cancer cells. Since there is very less evidence on oral cancer piperine strength the prospective to treat oral cancer as its usefulness for the above said molecular mechanism associate with other cancer. This shows the postern to piperine against oral cancer research. Further impost of the anticancer potency of piperine on in vivo and clinical trials need to be studied for anticancer drug development in oral cancer treatment.

Non-canonical anti-cancer, anti-metastatic, anti-angiogenic and immunomodulatory PDT potentials of water soluble phthalocyanine derivatives with imidazole groups and their intracellular mechanism of action

Cancer is currently a leading health issue globally. Chemotherapy is a prominent treatment method but due to undesired side effects t, there has been a need for novel less toxic approaches. Photodynamic therapy may be listed among the alternatives for efficient and potentially less detrimental applications of cancer therapy. Canonical photodynamic therapy (PDT) approach requires a light source with a specific wavelength of light, a non-toxic photosensitizer and molecular oxygen. PDT creates the desired effect by the photochemical reaction created through interaction of these components to create reactive oxygen species that will act on the cancer cells to enable anti-cancer activities. In our study we focus on non-canonical PDT application. In this approach we are not only aiming to eliminate cancer cells in the environment but also test the anti-metastatic, anti-angiogenic and possible immunomodulatory activities of the novel photosensitizers. Moreover, in our approach, we studied the intracellular pathways that are crucial for carcinogenesis, cell cycle, apoptosis, angiogenesis, metastasis and immune function to decipher the mechanism of the action for each compound. Reactive oxygen species based explanation was not valid in our study, hence it brings out a non canonical approach to PDT applications. Our results suggests that Phthalocyanine derivatives with imidazole groups can be effectively used against lung, colon, breast and prostate cancer while differentially effecting metastasis, angiogenesis, cell cycle, apoptosis and immune system cells’ activities. Based on the results, PDT application of these phthalocyanine derivatives can be an effective treatment option to replace chemotherapy to minimize the potential side effects.

Impact of Polypyridyl Ru Complexes on Angiogenesis-Contribution to Their Antimetastatic Activity.

The use of polypyridyl Ru complexes to inhibit metastasis is a novel approach, and recent studies have shown promising results. We have reported recently that Ru (II) complexes gathering two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and the one being 2,2′-bipyridine (bpy) or its derivative with a 4-[3-(2-nitro-1H-imidazol-1-yl)propyl (bpy-NitroIm) or 5-(4-{4′-methyl-[2,2′-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moieties can alter the metastatic cascade, among others, by modulating cell adhesion properties. In this work, we show further studies of this group of complexes by evaluating their effect on HMEC-1 endothelial cells. While all the tested complexes significantly inhibited the endothelial cell migration, Ru-bpy additionally interrupted the pseudovessels formation. Functional changes in endothelial cells might arise from the impact of the studied compounds on cell elasticity and expression of proteins (vinculin and paxillin) involved in focal adhesions. Furthermore, molecular studies showed that complexes modulate the expression of cell adhesion molecules, which has been suggested to be one of the factors that mediate the activation of angiogenesis. Based on the performed studies, we can conclude that the investigated polypyridyl Ru (II) complexes can deregulate the functionality of endothelial cells which may lead to the inhibition of angiogenesis.