Anti-invasive Effects Research Articles

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells.

Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

Reduction of invasion and cell stemness and induction of apoptotic cell death by Cinnamomum cassia extracts on human osteosarcoma cells.

Cinnamomum cassia possesses antioxidative activity and induces the apoptotic properties of various cancer types. However, its effect on osteosarcoma invasion and cancer stemness remains ambiguous. Here, we examined the molecular evidence of the anti-invasive effects of ethanoic C. cassia extracts (CCE). Invasion and migration were obviously suppressed after the expression of urokinase-type plasminogen activator and matrix metalloprotein 2 in human osteosarcoma 143B cells were downregulated. CCE reversed epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor β1 and downregulated mesenchymal markers, such as snail-1 and RhoA. CCE suppressed self-renewal property and the expression of stemness genes (aldehyde dehydrogenase, Nanog, and CD44) in the 143B cells. CCE suppressed cell viability, reduced the colony formation of osteosarcoma cancer cells, and induced apoptotic cell death in the 143B cells, as indicated by caspase-9 activation. The xenograft tumor model of immunodeficient BALB/c nude mice showed that CCE administered in vivo through oral gavage inhibited the growth of implanted 143B cells. These findings indicated that CCE inhibited the invasion, migration, and cancer stemness of the 143B cells. CCE reduced proliferation of 143B cell possibly because of the activation of caspase-9 and the consequent apoptosis, suggesting that CCE is a potential anticancer supplement for osteosarcoma.

Hypermethylation of microRNA-497-3p contributes to progression of thyroid cancer through activation of PAK1/β-catenin.

MicroRNA-497 (miR-497) has been reported to be a tumor-suppressive miRNA in thyroid cancer (TC), yet the mechanism is not clearly defined. In this study, we aim to determine the mechanism by which miR-497-3p affects the progression of TC. After characterization of low miR-497-3p expression pattern in TC and normal tissues, we assessed the correlation between miR-497-3p expression and clinicopathological features of TC patients. Its low expression shared associations with advanced tumor stage and lymph node metastasis. ChIP and methylation-specific PCR provided data showing that downregulation of miR-497-3p in TC tissues was induced by DNA methyltransferase-mediated hypermethylation. By performing dual-luciferase reporter assay, we identified that miR-497-3p targeted PAK1 while PAK1 could inhibit β-catenin expression. Through this mechanism, miR-497-3p exerted the anti-proliferative, anti-invasive, pro-apoptotic, and anti-tumorigenic effects on TC cells on the strength of the results from gain-of-function and rescue experiments. This study suggested that hypermethylation of miR-497-3p resulted in upregulation of β-catenin dependent on PAK1 and contributed to cancer progression in TC, which highlighted one of miR-mediated tumorigenic mechanism.

Cannabinoids as Prospective Anti-Cancer Drugs: Mechanism of Action in Healthy and Cancer Cells.

Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.

Hesperetin Inhibits TGF-β1-Induced Migration and Invasion of Triple Negative Breast Cancer MDA-MB-231 Cells via Suppressing Fyn/Paxillin/RhoA Pathway.

Triple-negative breast cancer is an aggressive subtype of breast cancer with poor clinical outcomes and poor prognosis. Hesperetin is an active component extracted from Citrus fruits and Traditional Chinese Medicine has a wide range of pharmacological effects. Here, we assessed the anti-migration and anti-invasive effects and explored inhibitory mechanisms of hesperetin on metastasis of human triple negative breast cancer MDA-MB-231 cells. Cell viability experiments revealed that 200 μM hesperetin has a clear inhibitory effect on MDA-MB-231 cells. TGF-β1 treatment induces apparent tumor progression in MDA-MB-231 cells including aberrant wound-healing and invasion ability, which is effectively suppressed by hesperetin co-treatment. Additionally, hesperetin inhibited the TGF-β1-mediated actin stress fiber formation. Western blot results showed that hesperetin suppressed the TGF-β1-mediated (i) activation of Fyn, (ii) phosphorylation of paxillin at Y31, Y88, and Y118 sites, (iii) the increased expression of RhoA, and (iv) activation of Rho-kinase. We demonstrated the increased interaction of Fyn with paxillin and RhoA protein in the TGF-β1-induced metastasis of MDA-MB-231 cells. Small interfering RNA Fyn inhibited phosphorylation of paxillin (Y31) and activation of Rho-kinase induced by TGF-β1. In conclusion, hesperetin has a significant inhibitory effect on migration and invasion of MDA-MB-231 cells induced by TGF-β1, which might be attributed to inhibiting the Fyn/paxillin/RhoA pathway.

Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-Induced Cytotoxicity: Impact in Non-Tumor Cells.

Doxorubicin (Dox) is one of the most widely used treatments for breast cancer, although limited by the well-documented cardiotoxicity and other off-target effects. Mesenchymal stem cell (MSC) secretome has shown immunomodulatory and regenerative properties, further potentiated under 3D conditions. This work aimed to uncover the effect of the MSC-derived secretome from 3D (CM3D) or 2D (CM2D) cultures, in human malignant breast cells (MDA-MB-231), non-tumor breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes, co-treated with Dox. A comprehensive proteomic analysis of CM3D/CM2D was also performed to unravel the underlying mechanism. CM3D/CM2D co-incubation with Dox revealed no significant differences in MDA-MB-231 viability when compared to Dox alone, whereas MCF10A and AC16 viability was consistently improved in Dox+CM3D-treated cells. Moreover, neither CM2D nor CM3D affected Dox anti-migratory and anti-invasive effects in MDA-MB-231. Notably, Ge-LC-MS/MS proteomic analysis revealed that CM3D displayed protective features that might be linked to the regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP8, PDCD5), invasion (TIMP1/2), oxidative stress (COX6B1, AIFM1, CD9, GSR) and inflammation (CCN3, ANXA5, CDH13, GDF15). Overall, CM3D decreased Dox-induced cytotoxicity in non-tumor cells, without compromising Dox chemotherapeutic profile in malignant cells, suggesting its potential use as a chemotherapy adjuvant to reduce off-target side effects.

Anti-Cancer Activity Profiling of Chemotherapeutic Agents in 3D Co-Cultures of Pancreatic Tumor Spheroids with Cancer-Associated Fibroblasts and Macrophages.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a five-year survival rate of less than 8%. There is a need to develop drugs with anti-invasive activity and in vitro tumor models for effective drug screening to improve patient outcomes. Since PDAC invasiveness is mainly induced by tumor-associated stromal cells, we aimed to develop a three-dimensional (3D) PDAC tumor model that mimics in vivo conditions. Additionally, we examined the usefulness of this model for evaluating chemotherapeutic drugs. We succeeded in establishing a 3D co-culture model of multicellular PDAC tumor spheroids, cancer-associated fibroblasts, and tumor-associated macrophages using a microfluidic channel chip platform. We also demonstrated the suitability of this model for evaluating cell-type dependent cytotoxicity, anti-invasive activity, and the association between the two. These results may help develop a novel system for screening the efficacy of chemotherapeutic drugs against PDAC and other solid tumors in the future.Activated pancreatic stellate cells (aPSCs) and M2 macrophages modulate tumor progression and therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC) via epithelial-mesenchymal transition (EMT). Here, our aim was to analyze the anti-invasion effects of anti-cancer agents where EMT-inducing cancer-stroma interaction occurs under three-dimensional (3D) culture conditions. We used microfluidic channel chips to co-culture pancreatic tumor spheroids (TSs) with aPSCs and THP-1-derived M2 macrophages (M2 THP-1 cells) embedded in type I collagen. Under stromal cell co-culture conditions, PANC-1 TSs displayed elevated expression of EMT-related proteins and increased invasion and migration. When PANC-1 TSs were exposed to gemcitabine, 5-fluorouracil, oxaliplatin, or paclitaxel, 30–50% cells were found unaffected, with no significant changes in the dose-response profiles under stromal cell co-culture conditions. This indicated intrinsic resistance to these drugs and no further induction of drug resistance by stromal cells. Paclitaxel had a significant anti-invasion effect; in contrast, oxaliplatin did not show such effect despite its specific cytotoxicity in M2 THP-1 cells. Overall, our findings demonstrate that the TS-stroma co-culture model of PDAC is useful for activity profiling of anti-cancer agents against cancer and stromal cells, and analyzing the relationship between anti-stromal activity and anti-invasion effects.

LncRNA SNHG14 accelerates breast cancer progression through sponging miR-543 and regulating KLF7 expression.

Dysregulation of long non-coding RNAs (lncRNAs) is being found to have relevance to human cancers, including breast cancer (BC). The aim of this study was to further explore the functional role and molecular mechanisms of small nucleolar RNA host gene 14 (SNHG14) on BC progression. The expression levels of SNHG14, miR-543, and krüppel-like factor 7 (KLF7) mRNA were determined by quantitative real-time PCR. Western blot analysis was used to evaluate KLF7 protein level. Cell proliferation, apoptosis, and migration and invasion abilities were detected by Cell Counting kit-8 assay, flow cytometry, and transwell assay, respectively. The direct interactions between miR-543 and SNHG14 or KLF7 were confirmed using dual-luciferase reporter assays. Our data indicated that SNHG14 expression was increased in BC tissues and cells, and SNHG14 knockdown mitigated the proliferation, migration, and invasion and facilitated apoptosis of BC cells. SNHG14 directly interacted with miR-543. MiR-543 mediated the regulatory effects of SNHG14 silencing on BC cell behaviors. Moreover, KLF7 was a direct target of miR-543. Overexpressed miR-543-mediated anti-proliferation, anti-migration, anti-invasion, and pro-apoptosis effects were mediated by KLF7. Furthermore, SNHG14 modulated KFL7 expression through acting as a competing endogenous RNA (ceRNA) of miR-543 in BC cells. Our study suggested that SNHG14 knockdown hindered BC progression in vitro at least partly through acting as a ceRNA of miR-543 and modulating KLF7 expression, providing evidence for SNHG14 as a potential target for BC therapy.

Bioactive compounds from Lactarius deterrimus interfere with the invasive potential of gastric cancer cells.

Stomach cancer is the 4th most common cancer diagnosed worldwide. Despite intensive research on its etiopathology, its treatment strategies have not changed in the last 50 years. Mushrooms have recently attracted much attention as the source of bioactive compounds that can potentially complement cancer therapies. Here, we extracted a phenolic fraction from Lactarius deterrimus and analyzed its composition and bioactivity against the gastric cancer (AGS) cells. The complexity of L. deterrimus compounds was revealed by an HPLC assay, and was accompanied by cytostatic, cytotoxic and anti-invasive effects of the L. deterrimus extract (LDE). These are illustrated by inhibition of the AGS cells' proliferation, metabolic activity and motility, and by induction of the cytoskeleton rearrangements. Apparently, these effects are exerted via activation of intracellular oxidative stress and decreased ATP production in AGS cells that could not be compensated by induction of autophagy. Less severe LDE effects were seen on physiology of normal gastric fibroblasts; however, inhibition of their motility indicates that LDE can interfere with gastric cancer development via an effect on stromal cells. Along with the observed synergy of LDE and cisplatin/5-fluorouracil effects on AGS cells, our data show the potential of LDE for supplementation of the gastric cancer therapy.

Targeting the Tumor Microenvironment: A Literature Review of the Novel Anti-Tumor Mechanism of Statins.

Statins is widely used in clinical practice as lipid-lowering drugs and has been proven to be effective in the treatment of cardiovascular, endocrine, metabolic syndrome and other diseases. The latest preclinical evidence shows that statins have anti-proliferation, pro-apoptotic, anti-invasion and radiotherapy sensitization effects on tumor cells, suggesting that statins may become a new type of anti-tumor drugs. For a long time, mevalonate pathway has been proved to play a supporting role in the development of tumor cells. As an effective inhibitor of mevalonate pathway, statins have been proved to have a direct auxiliary anti-tumor effect in a large number of studies. In addition, anti-tumor effects of statins through ferroptosis, pyroptosis, autophagy and tumor microenvironment (TME) have also been gradually discovered. However, the specific mechanism of the antitumor effect of statins in the tumor microenvironment has not been clearly elucidated. Herein, we reviewed the antitumor effects of statins in tumor microenvironment, focusing on hypoxia microenvironment, immune microenvironment, metabolic microenvironment, acid microenvironment and mechanical microenvironment.

Therapeutic effect of neohesperidin on TNF-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes.

During the pathogensis of rheumatoid arthritis (RA), activated RA fibroblast-like synoviocytes (RA-FLSs) combines similar proliferative features as tumor and inflammatory features as osteoarthritis, which eventually leads to joint erosion. Therefore, it is imperative to research and develop new compounds, which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression. Neohesperidin (Neo) is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties. In this study, the anti-inflammation, anti-migration, anti-invasion, anti-oxidant and apoptosis-induced effects of Neo on RA-FLSs were explored to investigate the underlying mechanism. The results suggested that Neo decreased the levels of interleukin IL-1β, IL-6, IL-8, TNF-α, MMP-3, MMP-9 and MMP-13 in FLSs. Moreover, Neo blocked the activation of the MAPK signaling pathway. Furthermore, treatment with Neo induced the apoptosis of FLSs, and inhibited the migration of FLSs. It was also found that Neo reduced the accumulation of reactive oxygen species (ROS) induced by TNF-α. Taken together, our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.

N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents: Synthesis and biological evaluation

Glioblastoma is one of the most lethal brain tumors. The crucial chemotherapy is mainly alkylating agents with modest clinical success. Given this desperate need and inspired by the encouraging results of a phase II trial via concomitant Topo I inhibitor plus COX-2 inhibitor, we designed a series of N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents based on structure modification on 1,5-naphthyridine derivatives (Topo I inhibitors). Notably, the target compounds I-1 (33.61 ± 1.15 μM) and I-8 (45.01 ± 2.37 μM) were confirmed to inhibit COX-2, while a previous reported compound (1,5-naphthyridine derivative) resulted nearly inactive towards COX-2 (IC50 > 150 μM). Besides, I-1 and I-8 exhibited higher anti-proliferation, anti-migration, anti-invasion effects than the parent compound 1,5-naphthyridine derivative, suggesting the success of modification based on the parent. Moreover, I-1 obviously repressed tumor growth in the C6 glioma orthotopic model (TGI = 66.7%) and U87MG xenograft model (TGI = 69.4%). Besides, I-1 downregulated PGE2, VEGF, MMP-9, and STAT3 activation, upregulated E-cadherin in the orthotopic model. More importantly, I-1 showed higher safety than temozolomide and different mechanism from temozolomide in the C6 glioma orthotopic model. All the evidence demonstrated that N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents could be promising for the glioma management.

Millettocalyxin B Inhibits Migratory Behavior of Lung Cancer Cells via Integrin α5 Suppression.

Integrin-targeting compounds have shown clinically significant benefits in many patients. Here, we examined the activity of millettocalyxin B, extracted from the stem bark of Millettia erythrocalyx, in lung cancer cells. The viability of human lung cancer cells was investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl tetrazoliumbromide (MTT) assay. Migration and invasion assays were performed. Phalloidin-rhodamine staining was used to determine the formation of filopodia. Western blot analysis and immunofluorescence staining were used to identify the signaling proteins involved in migration regulation. Non-toxic concentrations (0-25 μM) of millettocalyxin B reduced migration and invasion of lung cancer A549 cells. Filopodia were significantly reduced in millettocalyxin B-treated cells. The migration regulatory proteins including integrin α5, active FAK, active Akt, and Cdc42 were significantly decreased in Millettocalyxin B-treated cells. Our findings revealed a novel anti-migration and anti-invasion effects and the underlying mechanism of millettocalyxin B, which may be exploited for cancer treatment.

The Phagosome-Lysosome Fusion Is the Target of a Purified Quillaja saponin Extract (PQSE) in Reducing Infection of Fish Macrophages by the Bacterial Pathogen Piscirickettsia salmonis.

Piscirickettsia salmonis, the etiological agent of Piscirickettsiosis, is a Gram-negative and facultative intracellular pathogen that has affected the Chilean salmon industry since 1989. The bacterium is highly aggressive and can survive and replicate within fish macrophages using the Dot/Icm secretion system to evade the host’s immune response and spread systemically. To date, no efficient control measures have been developed for this disease; therefore, the producers use large amounts of antibiotics to control this pathogen. In this frame, this work has focused on evaluating the use of saponins from Quillaja saponaria as a new alternative to control the Piscirickettsiosis. It has been previously reported that purified extract of Q. saponaria (PQSE) displays both antimicrobial activity against pathogenic bacteria and viruses and adjuvant properties. Our results show that PQSE does not present antimicrobial activity against P. salmonis, although it reduces P. salmonis infection in an in vitro model, promoting the phagosome–lysosome fusion. Additionally, we demonstrate that PQSE modulates the expression of IL-12 and IL-10 in infected cells, promoting the immune response against the pathogen and reducing the expression of pathogen virulence genes. These results together strongly argue for specific anti-invasion and anti-intracellular replication effects induced by the PQSE in macrophages.

Cancer Preventive and Therapeutic Potential of Banana and Its Bioactive Constituents: A Systematic, Comprehensive, and Mechanistic Review

BackgroundThe banana (Musa spp.) plant produces elongated and edible fruit. The two main parthenocarpic species of banana are Musa accuminata Colla and Musa balbisiana Colla. There are several health-promoting and disease-preventing effects of Musa accuminata Colla, which are attributed to its important bioactive compounds, including phenolics, carotenoids, biogenic amines, phytosterols, and volatile oils, found in the stem, fruit, pseudostem, leaf, flower, sap, inner trunk, root, and inner core. Banana possesses numerous pharmacological activities, such as antioxidant, immunomodulatory, antimicrobial, antiulcerogenic, hypolipidemic, hypoglycemic, leishmanicidal, anthelmintic, and anticancer properties. Various individual studies have reported anticancer effects of different components of the banana plant. However, according to our understanding, an up-to-date, systematic, and critical analysis of existing scientific results has not yet been carried out.ObjectivesThis review aims to include a thorough assessment of banana and its phytochemicals for cancer prevention and therapy with a focus on cellular and molecular mechanisms of action.MethodsThe available research studies on anticancer activities of banana extracts, fractions and pure compounds were collected using various scholarly databases, such as PubMed, ScienceDirect, and Scopus, based on predetermined selection criteria.ResultsVarious banana extracts, fractions, and phytoconstituents, including ferulic acid, protocatechualdehyde, 2-pentanone, 4-epicyclomusalenone, cycloeucalenol acetate, and chlorogenic acid, have been shown to exhibit cancer preventative and anticancer activities in breast, cervical, colorectal, esophageal, hepatic, oral, prostate, and skin cancers. Bioactive components present in bananas have exhibited antiproliferative, cell cycle arrest-inducing, apoptotic, anti-adhesive, anti-invasive, and antiangiogenic effects through modulation of diverse, dysregulated oncogenic signaling pathways.ConclusionBased on the critical analysis of available literature, banana products and phytoconstituents show enormous potential for future development of drugs for cancer prevention and therapy. However, more mechanistic studies and well-designed clinical trials should be performed to establish its efficacy.

The Phytochemical Profile and Biological Activity of Liquidambar orientalis Mill. var. orientalis via NF-κB and Apoptotic Pathways in Human Colorectal Cancer

Liquidambar orientalis Mill. var. orientalis (Hammamelidaceae) commonly known as oriental sweet gum is a medicinal plant endemic to Turkey, and used for treatment of wounds such as ulcers, gastritis and skin diseases. However, there are only a limited number of studies on the anticancer properties of this plant. The aim of this study is to investigate the cellular and molecular mechanisms of L. orientalis in colorectal cancer cell lines and to reveal the active therapeutic components. Antioxidant, anti-proliferative, anti-invasive and apoptotic effects were investigated for determining biological activities. The phytochemical profile and quantitation assays were carried out by using HPLC-ESI-Q-TOF-MS. The results demonstrated that leaf methanol extract (LM) of L. orientalis has the highest cytotoxic activity in HCT-116 (IC50 27.80 μg/mL) and HT-29 (IC50 43.13 μg/mL) cell lines as compared to the other extracts tested. Regarding chemical composition, quercetin 3-glucoside (61.005 ± 1.527 mg/g extract), chlorogenic acid (31.627 ± 0.970 mg/g extract), pyrogallol (9.950 ± 0.001 mg/g extract), epigallocatechin gallate (9.671 ± 0.004 mg/g extract), apigenin 7-O-glucoside (2.687 ± 0.027 mg/g extract), gallic acid (2.137 ± 0.012 mg/g extract), genistin (1.270 ± 0.027 mg/g extract), luteolin (0.055 ± 0.0005 mg/g extract) and kaempferol (0.506 ± 0.007 mg/g extract) were identified as the major phytochemical compounds. Our results showed that LM extract exhibited In Vitro cytotoxic and apoptotic properties.

MiR-221 regulates proliferation, invasion, apoptosis and progression of prostate cancer cells by modulating E-cadherin/Wnt/β catenin axis

MicroRNA-221 (miR-221) is aberrantly expressed in various tumours including prostate carcinoma and can act as either tumour suppressor or oncogene depending on the tumour system and stage. Epithelial-mesenchymal transition (EMT) is a plastic transition in tumour progression characterized by decreased expression of epithelial markers and increased expression of mesenchymal markers and has been known to play a critical role in promoting metastases. In this study, we have demonstrated the functional role of miR-221 in regulating epithelial-mesenchymal transition in prostate cancer. Expression of miR-221 was found to be downregulated in androgen-independent prostate cancer cells and was found to be inversely correlated with EMT. Ectopic expression of miR-221 potentially inhibited invasion and migration of androgen-independent prostate cancers cells and inhibition of miR-221 expression rescued the anti-invasive effects of miR-221. Flow cytometric analysis further revealed that miR-221 could induce cell cycle arrest with simultaneous induction of apoptosis. Additionally, transfection with miR-221 mimic upregulated negative regulators of Wnt/β catenin pathway such as GSK-3β thereby inhibiting it and downregulated mesenchymal markers viz., N-cadherin and Vimentin with simultaneous upregulation of epithelial marker E-cadherin as revealed by real-time PCR and Western blot analysis. A study using xenograft model further confirmed the anti-tumorigenic and anti-metastatic role of miR-221 in prostate cancer. We believe that his study is the first report documenting the miR-221- Wnt/β catenin signaling-EMT regulatory circuit in prostate cancer.

Kaempferol inhibits the cell migration of human hepatocellular carcinoma cells by suppressing MMP-9 and Akt signaling.

Metastasis is the most prevalent cause of cancer-related deaths and treatment failure in patients with hepatocellular carcinoma (HCC). Kaempferol is a natural flavonol belonging to the subgroup of flavonoids and exhibits potent anticancer activities. This study provides molecular evidence on the anti-invasive and anti-migratory effects of kaempferol on human HCC cells. The anti-invasive effect was investigated by applying kaempferol on two human HCC cell lines (Huh-7 and SK-Hep-1). Kaempferol reduced the invasion and migration of Huh-7 and SK-Hep-1 cells by Boyden chamber invasion assay and wound healing assay, respectively. A protease array analysis showed that Matrix Metalloproteinase-9 (MMP-9) was dramatically downregulated in HCC cells after kaempferol treatment. Gelatin zymography and Western blot assay showed that kaempferol reduced the activities and protein expression of MMP-9, respectively. Kaempferol also sufficiently suppressed the phosphorylation of the Akt expression. Overall, kaempferol inhibited the invasive properties of human HCC cells by targeting MMP-9 and Akt pathways. Hence, kaempferol could be used as an adjuvant therapeutic agent for the treatment of human HCC cells.

Derrischalcone suppresses cholangiocarcinoma cells through targeting ROS-mediated mitochondrial cell death, Akt/mTOR, and FAK pathways.

Chemotherapy is a palliative treatment for unresectable patients with cholangiocarcinoma (CCA). However, drug resistance is a major cause of the failure of this treatment. Derrischalcone (DC), a novel chalcone isolated from Derris indica fruit, has been shown pharmacologically active; though, the effect of DC on CCA is unknown. The present study investigated the cytotoxic, antiproliferative, anti-migration, and anti-invasion effects and underlying mechanisms of DC on CCA KKU-M156 and KKU-100 cells. Cytotoxicity and apoptosis were evaluated by acridine orange and ethidium bromide fluorescent staining. Reactive oxygen species (ROS) was measured by dihydroethidium assay. Cell proliferation and reproductive cell death were assessed by sulforhodamine B staining and colony-forming assay. Migration and invasion were determined by wound healing and transwell chamber assays. Protein expressions associated with cell death, proliferation, migration, and invasion were analyzed by western immunoblotting. We found that DC induced cytotoxicity and apoptosis in association with ROS formation and oxidative stress. Treatment with N-acetylcysteine suppressed ROS formation and attenuated DC-induced cytotoxic and apoptotic effects. DC increased the expression of p53, p21, Bax, and cytochrome c proteins in association with cell death. DC-induced antiproliferation, colony formation, anti-migration, and anti-invasion were associated with the suppression of Akt/mTOR/cyclin D1 and FAK signaling pathways. These findings suggest that the multi-targeting strategies with DC may be a novel treatment for cancer therapy.