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Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti-cancer and anti-metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase-type plasminogen activator and matrix metalloproteinase-2. Gossypol reversed TGF-β-induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p-FAK, p-Src and p-paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice., (© 2024 Wiley Periodicals LLC.)

Invasiveness and epithelial-mesenchymal transition (EMT) are main patterns of metastatic disease, which is the major cause cancer-related mortality in human malignant melanoma cells. Tea and its consumption extract are associated with a lower risk of several types of cancer and have anti-inflammatory and antioxidative biological effects. However, the anti-EMT and anti-cancer stemness effect of black tea ethanol extracts (BTEE) in human melanoma remain poorly understood. In this study, the effects of BTEE-reduced invasiveness, EMT, and cancer stemness were evaluated in human A 375 and A2058 melanoma cells. BTEE inhibited the activity of u-PA, migration, and invasiveness by repressing p-FAK signaling pathway. BTEE affected the EMT by downregulating the expression of β-catenin, N-cadherin, fibronectin, vimentin, and Twist-1. BTEE also reduced tumor necrosis factor-alpha (TNF-α)-induced invasiveness and cancer stemness characteristics in vitro. The growth of melanoma in nude mice xenograft model showed that BTEE suppressed A 375 tumor growth in vivo., (© 2024 Wiley Periodicals LLC.)

Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon. Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose-dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose-dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK-mediated pro-caspases cleavage. Taken together, our results demonstrate that DSK has anti-cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38-mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management., (© 2024 Wiley Periodicals LLC.)

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti-tumor, anti-inflammatory, and anti-oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non-toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down-regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA-induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti-invasive effect of AA on osteosarcoma cells via the p-AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma., (© 2024 Wiley Periodicals LLC.)

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., (© 2022 Wiley Periodicals LLC.)

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., (© 2021 Wiley Periodicals LLC.)

Cantharidic acid (CA) is the hydrolysis product of the acid anhydride cantharidin, which is a natural toxin secreted by several species of blister beetles. Several studies have indicated that as an inhibitor of protein phosphatase 2 (PP2A), CA induces apoptosis in various human cancer cells. However, the effect of CA on human nasopharyngeal carcinoma (NPC) cells and the underlying pathways have not been addressed. In our current study, we tested the hypothesis that CA treatment reduces the viability of human NPC cells (HONE-1, NPC-39, and NPC-BM) by inducing apoptosis. Results indicated that CA markedly reduced cell viability, which was revealed by the upregulation of caspase activation in extrinsic and intrinsic apoptosis pathways as well as the upregulation of extracellular-signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2) pathways. Coadministration of a p38 inhibitor (SB203580) with CA abolished the activation of caspase proteins. These findings indicated that CA treatment leads to apoptosis in human NPC cells through the upregulation of caspase activation, mediated particularly by the p38 pathway. Hence, CA is a promising therapeutic agent for human NPC., (© 2020 Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti-inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen-activated protein kinase-related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase-8 and caspase-9, caspase-3 activation, and cleaved-poly ADP-ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co-administration of a JNK inhibitor (JNK-IN-8) or p38 inhibitor (SB203580) abolishes the activation of caspase-9, caspase-8, and caspase-3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells., (© 2019 Wiley Periodicals, Inc.)

Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM., (© 2018 Wiley Periodicals, Inc.)

The metastasis of oral squamous cell carcinoma (OSCC) is one of the most important causes of cancer-related deaths. Thus, various therapeutic strategies have been developed to prevent the metastasis of OSCC. Salvianolic acid A (SAA), a traditional Chinese medicine, has antithrombosis, antiplatelet, anti-inflammation, and antitumor activities. Here, we provide molecular evidence indicating that SAA exerts its antimetastatic effects by markedly inhibiting the invasion and migration of oral squamous SCC-9 and SCC-25 cells. SCC-9 and SCC-25 cells were treated with various concentrations of SAA to further investigate the precise involvement of SAA in cancer metastasis. The results of zymography, and Western blotting indicated that SAA treatment may decrease matrix metallopoteinase-2 (MMP-2) expression. SAA also inhibited p-c-Raf, p-MEK1/2, and p-ERK1/2 protein expression. In addition, treating SCC-9 cells with U0126, a MEK-specific inhibitor, decreased MMP-2 expression and concomitantly inhibited cell migration. Our findings suggested that SAA inhibits the invasion and migration of OSCC by inhibiting the c-Raf/MEK/ERK pathways that control MMP-2 expression. Our findings provide new insights into the molecular mechanisms that underlie the antimetastatic effect of SAA and are thus valuable for the development of treatment strategies for metastatic OSCC., (© 2018 Wiley Periodicals, Inc.)

Cantharidin analogs exhibit anticancer activities, including apoptosis. However, the molecular mechanisms underlying the effects of cantharidic acid (CA), a cantharidin analog, on apoptosis in hepatocellular carcinoma (HCC) cells are unclear. Thus, in this study, we evaluated the anticancer activities of CA by investigating its ability to trigger apoptosis in SK-Hep-1 cells. Our data demonstrated that CA effectively inhibited the proliferation of SK-Hep-1 cells in a dose-dependent manner. Furthermore, CA effectively triggered cell cycle arrest and induced apoptosis, as determined by flow cytometric analysis. Western blotting revealed that CA significantly activated proapoptotic signaling including caspase-3, -8, and -9 in SK-Hep-1 cells. Moreover, treatment of SK-Hep-1 cells with CA induced the activation of ERK, p38, and c-Jun N-terminal kinase. Moreover, the inhibition of p38 by specific inhibitors abolished CA-induced cell apoptosis. In conclusion, our results indicated that CA induces apoptosis in SK-Hep-1 cells through a p38-mediated apoptotic pathway and could be a new HCC therapeutic agent., (© 2017 Wiley Periodicals, Inc.)

Rheum palmatum L., a traditional Chinese medication, has been used for the treatment of various disorders. However, the detailed impacts and underlying mechanisms of R. palmatum L. extracts (RLEs) on human oral cancer cell metastasis are still unclear. Here, we tested the hypothesis that an RLE has antimetastatic effects on SCC-9 and SAS human oral cancer cells. Gelatin zymography, Western blot, real-time polymerase chain reaction, and luciferase assay were used to explore the underlying mechanisms involved in the antimetastatic effects on oral cancer cells. Our results revealed that the RLE (up to 20 μg/mL, without cytotoxicity) attenuated SCC-9 and SAS cell motility, invasiveness, and migration by reducing matrix metalloproteinase (MMP)-2 enzyme activities. Western blot analysis of the MAPK signaling pathway indicated that the RLE significantly decreased phosphorylated ERK1/2 levels but not p38 and JNK levels. In conclusion, RLEs exhibit antimetastatic activity against oral cancer cells through the transcriptional repression of MMP-2 via the Erk1/2 signaling pathways. Thus, RLEs may be potentially useful as antimetastatic agents for oral cancer chemotherapy., (© 2017 Wiley Periodicals, Inc.)

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., (© 2017 Wiley Periodicals, Inc.)

Tricetin, a dietary flavonoid, has cytostatic properties and anti-metastasis activities in various cancer cells. However, the detailed impacts and underlying mechanisms of tricetin on human osteosarcoma cell metastasis are still unclear. Here, the hypothesis that tricetin possesses the anti-metastatic effects on human osteosarcoma cells was tested. The effects of tricetin on cell viability, motility, migration, and invasion in human osteosarcoma U2OS and HOS cells were investigated. Gelatin zymography, western blotting, polymerase chain reaction (PCR), and the luciferase assay were used to further explore the underlying mechanisms involved in anti-metastatic effects in U2OS cells. Their results showed that Tricetin, up to 80 μM without cytotoxicity, attenuated U2OS and HOS cells motility, invasiveness, and migration by reducing matrix metalloproteinase (MMP)-9 enzyme activities. In U2OS cells, tricetin decreased MMP-9 protein and mRNA expressions, which was confirmed by real-time PCR. Next, tricetin reduced phosphorylation of p38 and Akt, but no effect on phosphorylation of ERK1/2 and JNK. In conclusion, tricetin possesses the anti-metastatic activity of osteosarcoma cells by transcriptionally repressing MMP-9 via p38 and Akt signaling pathways. This may be potentially useful as anti-metastatic agents for osteosarcoma chemotherapy., (© 2016 Wiley Periodicals, Inc.)

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)-β1-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-β1-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., (© 2017 Wiley Periodicals, Inc.)

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and the major cause of mortality in urological cancer. Most patients with RCC are asymptomatic until the disease is advanced and unresectable. In this situation, systemic therapy with immunotherapy or molecularly targeted therapy agents play an important role in therapeutic strategy. Everolimus (EVE), an m-TOR inhibitor, has the potential to inhibit tumor progression at multiple levels and is indicated for the treatment of advanced RCC in patients whose disease has metastasis. In this study, we provide molecular evidence associated with the antimetastatic effect of everolimus by demonstrating the suppression of lung metastasis of 786-O cells in mouse model. This effect was associated with reduced protein expressions of p-FAK (Tyr 925), p-Src (Tyr416), Vimentin, and RhoA and also with increased the E-cadherin protein expression. In summary, these findings provide new insights into the molecular mechanisms involved in the antimetastatic effect of everolimus and are thus valuable in the treatment of metastatic RCC., (© 2017 Wiley Periodicals, Inc.)

Raspberries (Rubus idaeus L.) have been extensively studies worldwide because of their beneficial effects on health. Recently reports indicate that crude extracts of Rubus idaeus (RIE) have antioxidant and anticancer ability. The aim of this study was to evaluate the mechanism of its antimetastatic ability in oral cancer cells. In this study, SCC-9 and SAS oral cancer cells were subjected to a treatment with RIE and then analyzed the effect of RIE on migration and invasion. The addition of RIE inhibited the migration and invasion ability of oral cancer cells. Real time PCR, western blot and zymography analysis demonstrated that mRNA, protein expression and enzyme activity of matrix metalloproteinases-2 (MMP-2) were down-regulated by RIE. Moreover, the phosphorylation of Focal adhesion kinase (FAK), src, and extracellular signal-regulated kinase (ERK) were inhibited after RIE treatment. In conclusion, these results demonstrated that RIE exerted an inhibitory effect of migration and invasion in oral cancer cells and alter metastasis by suppression of MMP-2 expression through FAK/Scr/ERK signaling pathway. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1037-1046, 2017., (© 2016 Wiley Periodicals, Inc.)