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 ß1 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.

Induction of apoptotic but not autophagic cell death by Cinnamomum cassia extracts on human oral cancer cells.

Cinnamomum cassia has been widely studied in different fields to reveal its antidiabetic, antidepressive, antiviral, anti-inflammatory, antiosteoporotic, and anticancer effects. Its antimalignant activities have been explored in lung cancer, breast cancer, colorectal cancer, and even oral cancer, but the detailed signaling mechanism and effects of this plant on animal models need to be clarified. In the current study, C. cassia extract (CCE) was used to investigate the antitumorigenesis mechanism in vitro and in vivo. The major constituents of CCE used in this study were coumarin, cinnamic acid, and cinnamic aldehyde. CCE reduced the viability, number, and colony formation of human oral cancer cells, and induced their apoptosis. Caspase-3 activation, Bcl-2 reduction, and phosphatidylserine inversion were involved in CCE-stimulated apoptosis. CCE also enhanced the expression of autophagic markers, including acidic vesicular organelle, microtubule-associated protein 1 light chain 3-I, autophagy-related protein 14, rubicon, and p62. The combined treatment of CCE and caspase inhibitor significantly restored mitochondrial membrane potential (Δ ψ m ) and cell viability. However, the combined treatment of CCE and autophagy inhibitor further reduced the cell viability indicating that autophagy might be a survival pathway of CCE-treated SASVO3 cells. In contrast, CCE treatment for 12 days did not adversely affect SASVO3 tumor-bearing nude mice. CCE also elicited dose-dependent effects on the decrease in tumor volume, tumor weight, and Ki-67 expression. These results suggested that CCE showed the potential for the complementary treatment of oral caner.

Thymoquinone suppresses the proliferation of renal cell carcinoma cells via reactive oxygen species-induced apoptosis and reduces cell stemness.

Thymoquinone is a phytochemical compound isolated from Nigella sativa and has various biological effects, including anti-inflammation, antioxidation, and anticancer. Here, we further investigated the anticancer effects and associated molecular mechanism of 2-methyl-5-isopropyl-1,4-benzoquinone (thymoquinone) on human renal carcinoma cell lines 786-O and 786-O-SI3 and transitional carcinoma cell line BFTC-909. Results showed that thymoquinone significantly reduced cell viability, inhibited the colony formation of renal cancer cells, and induced cell apoptosis and mitochondrial membrane potential change in both cancer cells. In addition, thymoquinone also triggered the production of reactive oxygen species (ROS) and superoxide and the activation of apoptotic and autophagic cascade. ROS inhibition suppressed the caspase-3 activation and restored the decreased cell viability of 786-O-SI3 in response to thymoquinone. Autophagy inhibition did not restore the cell viability of 786-O-SI3 suppressed by thymoquinone. Moreover, thymoquinone suppressed the cell sphere formation and the expression of aldehyde dehydrogenase, Nanog, Nestin, CD44, and Oct-4 in 786-O-SI3 cells. The tumor-bearing model showed that thymoquinone in vivo inhibited the growth of implanted 786-O-SI3 cell. All these findings indicate that thymoquinone inhibits the proliferation of 786-O-SI3 and BFTC-909 cell possibly due to the induction of ROS/superoxide and the consequent apoptosis, suggesting that thymoquinone may be a potential anticancer supplement for genitourinary cancer.

Role of hypothalamic leptin-LepRb signaling in NPY-CART-mediated appetite suppression in amphetamine-treated rats.

Leptin is an adipose tissue hormone which plays an important role in regulating energy homeostasis. Amphetamine (AMPH) is a drug of appetite suppressant, which exerts its effect by decreasing the expression of hypothalamic neuropeptide Y (NPY) and increasing that of cocaine- and amphetamine-regulated transcript (CART). This study investigated whether leptin, the leptin receptor (LepRb) and the signal transducer and activator of transcription-3 (STAT3) were involved in NPY/CART-mediated appetite suppression in AMPH-treated rats. Rats were given AMPH daily for four days, and changes in the levels of blood leptin and hypothalamic NPY, CART, LepRb, Janus kinases 2 (JAK2), and STAT3 were assessed and compared. During the AMPH treatment, blood leptin levels and hypothalamic NPY expression decreased, with the largest reduction observed on Day 2. By contrast, the expression of hypothalamic CART, LepRb, JAK2, and STAT3 increased, with the maximum response on Day 2. Furthermore, the binding activity of pSTAT3/DNA increased and was expressed in similar pattern to that of CART, LepRb, and JAK2. An intracerebroventricular infusion of NPY antisense 60min prior to AMPH treatment increased the levels of leptin, as well as the expression in LepRb, JAK2, and CART, whereas an infusion of STAT3 antisense decreased these levels and the expression of these parameters. The results suggest that blood leptin and hypothalamic LepRb-JAK2-STAT3 signaling involved in NPY-CART-regulated appetite suppression in AMPH-treated rats. The findings may aid understanding the role of leptin-LepRb during the treatment of anorectic drugs.

Viola Yedoensis Suppresses Cell Invasion by Targeting the Protease and NF-κB Activities in A549 and Lewis Lung Carcinoma Cells.

Cancer metastasis is a vital trait in malignancies with complicated early diagnosis and therapeutic management. Therefore, the development of new remedies and the utilization of natural medicines that target metastasis are of great interest and have been studied extensively. Chinese medicinal herbs have various anti-carcinogenesis properties; however, the in vitro effect and mechanism of Viola yedoensis on cancer cell metastasis remains poorly understood. V. yedoensis extracts (VYE) can suppress the invasion of a highly metastatic human lung cancer cell line, A549 cells. According to gelatin zymography and casein zymography assays, VYE inhibited the activities of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (u-PA). The results of reverse transcription-polymerase chain reaction and Western blotting revealed that VYE can alter the expression of proteinase inhibitor. VYE also suppressed the DNA binding activity of nuclear factor-kappa B. We concluded that VYE may inhibit tumor invasion by suppressing the activities of MMP and u-PA in lung cancer cells.

Cinnamomum Cassia Extracts Suppress Human Lung Cancer Cells Invasion by Reducing u-PA/MMP Expression through the FAK to ERK Pathways.

Cinnamomum cassia exhibits antioxidative, apoptotic, and cytostatic properties. These activities have been attributed to the modulation of several biological processes and are beneficial for possible pharmaceutical applications. However, the potential of C. cassia in retarding lung adenocarcinoma cells metastasis remains ambiguous. We determined whether C. cassia extract (CCE) reduces metastasis of human lung adenocarcinoma cells. The results showed that CCE treatment (up to 60 µg/mL) for 24 h exhibited no cytotoxicity on the A549 and H1299 cell lines but inhibited the motility, invasiveness, and migration of these cells by repressing matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA). CCE also impaired cell adhesion to collagen. CCE significantly reduced p-focal adhesion kinase (FAK) Tyr397, p-FAK Tyr925, p-extracellular signal-regulated kinases (ERK)1/2, and Ras homolog gene family (Rho)A expression. CCE showed anti-metastatic activity of A549 and H1299 cells by repressing u-PA/MMP-2 via FAK to ERK1/2 pathways. These findings may facilitate future clinical trials of lung adenocarcinoma chemotherapy to confirm the promising results.

Koelreuteria Formosana Extract Induces Growth Inhibition and Cell Death in Human Colon Carcinoma Cells via G2/M Arrest and LC3-II Activation-Dependent Autophagy.

Autophagy is a self-destructive process that degrades cytoplasmic constituents. In our previous study, Koelreuteria formosana ethanolic extract (KFEE), which is obtained from natural plants endemic to Taiwan, has inhibited cell metastasis in renal carcinoma cells. However, the anticancer effects of KFEE on colon cancer remain unclear. In this study, KFEE exerted a strong cytotoxic effect on DLD-1 and COLO 205 human colorectal cancer cell lines. KFEE effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with downregulaton of cyclin E, cyclin B and cdc25C and upregulation of p21, and induced cell death by activating autophagy but did not cause apoptotic cell death. Exposed KFEE cells showed increased levels of acridine orange, autophagic vacuoles, and LC3-II proteins, which are specific autophagic markers. Bcl-2, p-Akt, and p-mTOR levels, which have been implicated in autophagic downregulation, were decreased after KFEE treatment. Autophagy inhibitor 3-methyladenosine and bafilomycin-A1 and genetic silencing of LC3 attenuated KFEE-induced growth inhibition. These findings suggested that KFEE causes cytostatic effect through autophagy. In xenograft studies, oral administration of KFEE had significantly inhibited the tumor growth in nude mice that had received subcutaneous injection of DLD-1 cells. KFEE is a promising candidate in phytochemical-based, mechanistic, and pathway-targeted cancer prevention strategies.

Participation of ghrelin signalling in the reciprocal regulation of hypothalamic NPY/POMC-mediated appetite control in amphetamine-treated rats.

Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) have been documented to participate in amphetamine (AMPH)-induced appetite suppression. This study investigated whether ghrelin signalling is associated with changes in NPY/POMC-mediated appetite control. Rats were given AMPH daily for four days, and changes in food intake, body weight, plasma ghrelin, hypothalamic NPY, melanocortin 3 receptor (MC3R), ghrelin O-acyltransferase (GOAT), acyl ghrelin (AG) and ghrelin receptor (GHSR1a) were examined and compared. Food intake, body weight and NPY expression decreased, while MC3R expression increased and expressed reciprocally to NPY expression during AMPH treatment. Plasma ghrelin and hypothalamic AG/GOAT/GHSR1a expression decreased on Day 1 and Day 2, which was associated with the positive energy metabolism, and returned to normal levels on Day 3 and Day 4, which was associated with the negative energy metabolism; this expression pattern was similar to that of NPY. Infusion with a GHSR1a antagonist or an NPY antisense into the brain enhanced the decrease in NPY and AG/GOAT/GHSR1a expression and the increase in MC3R expression compared to the AMPH-treated group. Peripheral ghrelin and the central ghrelin system participated in the regulation in AMPH-induced appetite control. These results shed light on the involvement of ghrelin signalling in reciprocal regulation of NPY/POMC-mediated appetite control and may prove useful for the development of anti-obesity drugs.

Cinnamomum cassia extracts reverses TGF-ß1-induced epithelial-mesenchymal transition in human lung adenocarcinoma cells and suppresses tumor growth in vivo.

Metastasis is the most common cause of cancer-related mortality in patients, and epithelial-mesenchymal transition (EMT) is essential for cancer metastasis and antidrug resistance. Cinnamomum cassia has several antioxidative, anti-inflammatory, and anticancer biological effects. However, the anti-EMT effect of C. cassia in human lung carcinoma is rarely reported. In this study, we determined whether C. cassia extracts (CCE) reduces the EMT and tumor growth of human lung adenocarcinoma cells. CCE inhibited the transforming growth factor (TGF)-ß1-induced cell motility and invasiveness of A549 and H1299 cells by repressing matrix metalloproteinase-2 and urokinase-type plasminogen activator as well as impaired cell adhesion to collagen. CCE also affected the TGF-ß1-induced EMT by downregulating the expression of vimentin and fibronectin and upregulating E-cadherin. The nude mice xenograft model showed that CCE reduced A549 tumor growth. Thus, CCE possesses antimetastatic activity of A549 and H1299 cells by affecting EMT and suppressing A549 tumor growth in vivo. This result suggested that CCE could be used as an antimetastatic agent or as an adjuvant for anticancer therapy.

Duchesnea indica extract suppresses the migration of human lung adenocarcinoma cells by inhibiting epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a process through which epithelial cells are transformed into mesenchymal cells; EMT diminishes cell polarity and cell-cell adhesion in cancer cells, leading to enhanced migratory and invasive properties. In this experiment, zymography, cell invasion, and migration assays were performed. Results indicated that Duchesnea indica extracts (DIE) inhibited highly metastatic A549 and H1299 cells by reducing the secretions of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Cell adhesion assay also demonstrated that DIE reduced the cell adhesion properties. Western blot analysis showed that DIE down-regulated the expression of N-cadherin, fibronectin, and vimentin, which are mesenchymal markers, and enhanced that of E-cadherin, which is an epithelial marker. In vivo study showed that tumor growth was significantly reduced in BALB/c nude mouse xenograft model administered with oral gavage of DIE. Therefore, DIE could be exhibits potential as a phytochemical-based platform for prevention and treatment of lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2053-2063, 2017.

Both neuropeptide Y knockdown and Y1 receptor inhibition modulate CART-mediated appetite control.

Amphetamine (AMPH)-induced appetite suppression has been attributed to its inhibition of neuropeptide Y (NPY)-containing neurons in the hypothalamus. This study examined whether hypothalamic cocaine- and amphetamine-regulated transcript (CART)-containing neurons and NPY Y1 receptor (Y1R) were involved in the action of AMPH. Rats were treated daily with AMPH for four days, and changes in feeding behavior and expression levels of NPY, CART, and POMC were assessed and compared. The results showed that both feeding behavior and NPY expression decreased during AMPH treatment, with the biggest reduction occurring on Day 2. By contrast, the expression of CART and melanocortin 3 receptor (MC3R), a member of the POMC neurotransmission, increased with the maximum response on Day 2, directly opposite to the NPY expression results. The intracerebroventricular infusion of NPY antisense or Y1R inhibitor both modulated AMPH-induced anorexia and the expression levels of MC3R and CART. The results suggest that in the hypothalamus both POMC- and CART-containing neurons participate in regulating NPY-mediated appetite control during AMPH treatment. These results may advance the knowledge of molecular mechanism of anorectic drugs.

Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells.

Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-ß1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.

2'-hydroxyflavanone induces apoptosis of human osteosarcoma 143 B cells by activating the extrinsic TRAIL- and intrinsic mitochondria-mediated pathways.

Flavanones demonstrate a propensity to antiproliferation and induce apoptosis of malignant cells. Among the 4 flavanones under study, 2'-hydroxyflavanone exhibited the greatest potency to reduce the cell viability of 143 B cells in 4 osteosarcoma cells. Flow cytometry analysis showed that 2'-hydroxyflavanone increased the hypodiploid cells in the sub-G1 phase but resulted in the reduced DNA content in the G0/G1 phase in 143 B cells. The 2'-hydroxyflavanone-induced apoptosis in 143 B cells was confirmed by 4'-6-diamidino-2-phenylindole staining and mitochondrial membrane potential (Δψm) assay. Increasing expressions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor 5 (DR5) were found in 2'-hydroxyflavanone-treated cells. Moreover, 2'-hydroxyflavanone increased the expressions of B-cell lymphoma-extra small, cytochrome c, and cleavage poly (ADP-ribose) polymerase but downregulated B-cell lymphoma/leukemia-2expressions in 143 B cells. Furthermore, in vivo experiments showed that 2'-hydroxyflavanone inhibited the tumor growth of 143 B cells. 2'-hydroxyflavanone induced the apoptosis of 143 B cells via the extrinsic TRAIL- and intrinsic mitochondrial-dependent pathways, indicating its potential for inducing cancer apoptosis in osteosarcoma.

The impact of IGF-I gene polymorphisms on coronary artery disease susceptibility.

BACKGROUND: Coronary artery disease (CAD) was the second leading cause of death for the past 3 years in Taiwan. The insulin-like growth factor (IGF) system is considered a new risk factor of CAD because investigations show that the levels and bioactivity of IGF-I and IGFBP-3 (where IGFBP is insulin-like growth factor-binding protein) may be involved in elevating the risk of CAD. This study investigated the relationships among IGF-I +1770, IGF-I +6093, and IGFBP-3 -202 genetic polymorphisms and CAD in the Taiwanese population. METHODS: A total of 581 subjects, including 390 non-CAD controls and 191 patients with CAD, were recruited and the isolated DNA was subjected to real-time polymerase chain to evaluate the effects of these three polymorphic variants on CAD. RESULTS: Our results showed a significant association between the IGF-I +1770 gene polymorphism and increased risk of CAD. Furthermore, CAD patients with a minimum of one mutant C allele, T/C or C/C, in IGF-I +1770 gene polymorphism had significantly high blood pressure including systolic blood pressure (SBP; P = 0.025) and diastolic blood pressure (DBP; P = 0.004), compared to CAD patients with T/T homozygotes. Moreover, CAD patients with a minimum of one mutant A allele, G/A or A/A, in the IGF-I +6093 gene polymorphism had a 1.695-fold elevated risk of congestive heart failure (CHF), compared to CAD patients with the G/G homozygote. CONCLUSIONS: Polymorphism of IGF-I +1770 was associated with increased CAD risk. In CAD patients, the contributions of IGF-I +1770 and +6093 could be through the effect on blood pressure in CAD patients.

Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility.

Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.

Knocking down the transcript of NF-kappaB modulates the reciprocal regulation of endogenous antioxidants and feeding behavior in phenylpropanolamine-treated rats.

It has been reported that oxidative stress, antioxidants, and neuropeptide Y (NPY) are involved in regulating the feeding behavior of phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether transcription factor NF-κB is involved in this effect. Rats were treated daily with PPA for 4 days. Changes in hypothalamic NF-κB, NPY, superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels during PPA treatment were assessed and compared. Results showed that NF-κB, SOD, and GPx increased, with a maximal response on Day 2, while the food intake and NPY decreased with the biggest reduction on Day 2 during PPA treatment. To further determine whether NF-κB was involved, intracerebroventricular infusion of antisense oligonucleotide was performed at 1 h before daily PPA in free-moving rats. Cerebral NF-κB knockdown could modify PPA anorexia and the expressions of NPY, SOD, and GPx. It is suggested that hypothalamic NF-κB participates in the reciprocal regulation of NPY and antioxidants, which mediated the appetite-suppressing effect of PPA. Results may further the understanding of the molecular mechanisms of PPA.

Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and ß-catenin pathway in vitro.

Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified. Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and ß-catenin. Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and ß-catenin. Conclusion: Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/ß-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.

Corrigendum: Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and ß-catenin pathway in vitro.

[This corrects the article DOI: 10.3389/fphar.2022.963589.].

Cinnamaldehyde decreases the invasion and u-PA expression of osteosarcoma by down-regulating the FAK signalling pathway.

Cancer metastasis is the major cause of the high mortality risk of patients with osteosarcoma. Cinnamaldehyde has been shown to exhibit multiple tumour-suppressing activities, but its role in human osteosarcoma is not yet completely defined. In this study, the antimetastatic effect of cinnamaldehyde on highly metastatic human osteosarcoma cells was observed in vitro and in vivo using Saos-2 and 143B cells. Cinnamaldehyde reduced the activity and protein level of urokinase-type plasminogen activator (u-PA) and suppressed the invasion ability of osteosarcoma cells by inhibiting the phosphorylation of focal adhesion kinase. In addition, cinnamaldehyde reduced cell movement, cell-matrix adhesion, and the expression of the mesenchymal markers of epithelial-to-mesenchymal transition, namely, fibronectin and N-cadherin. Importantly, the oral administration of cinnamaldehyde remarkably suppressed the pulmonary metastasis of osteosarcoma in mice. Results indicated that cinnamaldehyde has therapeutic potential for inhibiting osteosarcoma metastasis.

A Cohort Study: Comorbidity and Stage Affected the Prognosis of Melanoma Patients in Taiwan.

Background: Comorbidities and stages may influence the prognosis of melanoma patients in Taiwan and need to be determined. Methods: We performed a retrospective cohort study by using the national health insurance research database in Taiwan. Patients with a primary diagnosis of melanoma by the Taiwan Cancer Registry from 2009 to 2017 were recruited as the study population. The comparison group was never diagnosed with melanoma from 2000 to 2018. The Charlson comorbidity index was conducted to calculate the subjects' disease severity. The Cox proportional hazards model analysis was used to estimate the hazard ratio of death. Results: We selected 476 patients, 55.5% of whom had comorbidity. A higher prevalence of comorbidity was associated with a more advanced cancer stage. The mortality rate increased with an increasing level of comorbidity in both cohorts and was higher among melanoma patients. The interaction between melanoma and comorbidity resulted in an increased mortality rate. Conclusion: An association between poorer survival and comorbidity was verified in this study. We found that the level of comorbidity was strongly associated with mortality. A higher risk of mortality was found in patients who had localized tumors, regional metastases, or distant metastases with more comorbidity scores. Advanced stage of melanoma patients with more comorbidities was significantly associated with the higher risk of mortality rate.