The anticancer activity of cationic antimicrobial peptides (AMPs) has become more interesting because some AMPs have selective recognition against cancer cells. However, their antitumor properties ...and underlying mechanisms in cancer cells have not been clearly understood. In this study, we evaluated the effects of KT2 (lysine/tryptophan‐rich AMP) on the cellular uptake and internalization mechanism, cell viability, surface charge of the cell membrane, membrane integrity, apoptotic cell death, and autophagy in human HCT 116 colon cancer cells. We found that KT2 interacted with the cell membrane of HCT 116 cells and was internalized into HCT 116 cells via clathrin‐mediated and caveolae‐mediated endocytosis mechanisms. The interaction of KT2 with cells caused cell membrane structure change, elevated membrane permeability, and KT2 also affected the lipid component. The results of atomic force microscopy showed cellular membrane defects of KT2‐treated cells. The internalized KT2 induced nuclear condensation and apoptotic cell death. It elevated the apoptotic factor levels including those of cytochrome c and apoptosis‐inducing factor. Furthermore, KT2 inhibited autophagy by the suppression of autophagy‐related 5, autophagy‐related 7, autophagy‐related 16 like 1, and Beclin‐1 proteins. In conclusion, these results revealed the cytotoxicity of cationic KT2 against HCT 116 cells and may help to clarify the interactions between cationic AMPs and cancer cells.
Our findings showed that KT2 interacts with the plasma membrane and is then internalized into cells. Moreover, the KT2 peptide increases membrane permeability and induces cytotoxicity against cancer cells through DNA condensation, the increase of apoptotic factor protein levels, and autophagy suppression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim of the present study is to investigate anticancer effect and mechanism of regorafenib in bladder cancer in vitro and in vivo. Human bladder cancer TSGH 8301 cells were treated with ...regorafenib, NF‐κB, AKT, or mitogen‐activated protein kinase (MAPK) inhibitors for different time. The changes of cell viability, NF‐κB activation, apoptotic signaling transduction, and expression of tumor progression‐associated proteins were evaluated with MTT, NF‐κB reporter gene assay, flow cytometry, and Western blotting assay. TSGH 8301 tumor bearing mice were established and treated with vehicle (140 μL of 0.1% DMSO) or regorafenib (10 mg/kg/day by gavage) for 15 days. The changes of tumor volume, body weight, NF‐κB activation, MAPK activation, and tumor progression‐associated proteins (MMP‐9, XIAP, VEGF, and Cyclin‐D1) after regorafenib treatment were evaluated with digital caliper, digital weight, and ex vivo Western blotting assay. Our results demonstrated NF‐κB activation and protein levels of MMP‐9, XIAP, VEGF, and Cyclin‐D1 were significantly reduced by NF‐κB (QNZ), ERK (PD98059), and P38 (SB203580) inhibitors. Regorafenib also significantly induced extrinsic and intrinsic apoptotic signaling transduction in bladder cancer in vitro. In addition, regorafenib significantly inhibited tumor growth, NF‐κB, p38, ERK activation and expression of tumor progression‐associated proteins in bladder cancer in vitro and in vivo. Taken together, these results proved that regorafenib not only induced apoptosis through extrinsic and intrinsic pathways and but suppressed MAPK/ NF‐κB‐modulated tumor progression in bladder cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Quercetin is one of the natural components from natural plant and it induces cell apoptosis in many human cancer cell lines. However, no available reports show that quercetin induces apoptosis and ...altered associated gene expressions in human gastric cancer cells, thus, we investigated the effect of quercetin on the apoptotic cell death and associated gene expression in human gastric cancer AGS cells. Results indicated that quercetin induced cell morphological changes and reduced total viability via apoptotic cell death in AGS cells. Furthermore, results from flow cytometric assay indicated that quercetin increased reactive oxygen species (ROS) production, decreased the levels of mitochondrial membrane potential (ΔΨm), and increased the apoptotic cell number in AGS cells. Results from western blotting showed that quercetin decreased anti‐apoptotic protein of Mcl‐1, Bcl‐2, and Bcl‐x but increased pro‐apoptotic protein of Bad, Bax, and Bid. Furthermore, quercetin increased the gene expressions of TNFRSF10D (Tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain), TP53INP1 (tumor protein p53 inducible nuclear protein 1), and JUNB (jun B proto‐oncogene) but decreased the gene expression of VEGFB (vascular endothelial growth factor B), CDK10 (cyclin‐dependent kinase 10), and KDELC2 (KDEL Lys‐Asp‐Glu‐Leu containing 2) that are associated with apoptosis pathways. Thus, those findings may offer more information regarding the molecular, gene expression, and signaling pathway for quercetin induced apoptotic cell death in human gastric cancer cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that ...Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.
The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.
The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.
The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Although hepatitis B and/or hepatitis C virus were recognized as major risk factor for the development of hepatocellular carcinoma (HCC), certain occupational, environmental, and lifestyle factors ...also play key roles in HCC tumorigenesis. Moreover, in molecular signaling route, extracellular signal‐regulated kinase (ERK)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling was found to be overexpressed and linked to poor prognosis in HCC. Thus, to identify possible nature compound that can suppress ERK/NF‐κB may be benefit to HCC patient. Magnolol, a natural compound derived from herbal plant Magnolia officinalis, has been recognized as a liver protection and antitumor reagent. However, whether magnolol‐inhibited HCC progression correlates with disruption of ERK/NF‐κB signaling is remained unclear. In this studies, we performed SK‐Hep1/luc2 HCC bearing animal model to investigate the anticancer efficacy and mechanism of magnolol on tumor progression. Tumor size and tumor growth rate were dramatically suppressed after treatment of magnolol. In addition, expression of phospho‐ERK (p‐ERK), NF‐κB p65 (Ser536), and tumor progression‐associated proteins, such as matrix metallopeptidase 9 (MMP‐9), vascular endothelial growth factor (VEGF), X‐linked inhibitor of apoptosis protein (XIAP), and CyclinD1 were all significantly decreased by magnolol. Most important, major extrinsic and intrinsic apoptosis signaling factors, including active caspase‐8 and caspase‐9 were both enhanced by magnolol. This study indicated that apoptosis induction through extrinsic/intrinsic pathways and blockage of ERK/NF‐κB activation were associated with magnolol‐inhibited tumor progression in HCC in vivo.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Genistein, a major isoflavone compound in soybeans, has been shown to have biological activities including anti‐cancer activates. In the present, we investigated the anti‐leukemia activity of ...genistein on HL‐60 cells in vitro. The percentage of viable cell, cell cycle distribution, apoptotic cell death, reactive oxygen species (ROS), and Ca2+ production and the level of ΔΨm were measured by flow cytometric assay. Cell apoptosis and endoplasmic reticulum (ER) stress associated protein expressions were examined by Western blotting assay. Calpain 1, GRP78, and GADD153 expression were measured by confocal laser microscopy. Results indicated that genistein‐induced cell morphological changes, decreased the total viable cells, induced G2/M phase arrest and DNA damage and fragmentation (cell apoptosis) in HL‐60 cells. Genistein promoted ROS and Ca2+ productions and decreased the level of ΔΨm in HL‐60 cells. Western blotting assay demonstrated that genistein increased ER stress‐associated protein expression such as IRE‐1α, Calpain 1, GRP78, GADD153, caspase‐7, caspase‐4, and ATF‐6α at 20‐50 μM treatment and increased apoptosis associated protein expression such as pro‐apoptotic protein Bax, PARP‐cleavage, caspase‐9, and ‐3, but decreased anti‐apoptotic protein such as Bcl‐2 and Bid in HL‐60 cells. Calpain 1, GRP78, and GADD153 were increased in HL‐60 cells after exposure to 40 μM of genistein. In animal xenografted model, mice were intraperitoneally injected with genistein (0, 0.2, and 0.4 mg/kg) for 28 days and the body weight and tumor volume were recorded. Results showed that genistein did not affect the body weights but significantly reduced the tumor weight in 0.4 mg/kg genistein‐treated group. Genistein also increased the expressions of ATF‐6α, GRP78, Bax, Bad, and Bak in tumor. In conclusion, genistein decreased cell number through G2/M phase arrest and the induction of cell apoptosis through ER stress‐ and mitochondria‐dependent pathways in HL‐60 cells and suppressed tumor properties in vivo.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Oral squamous cell carcinoma (OSCC) is the fifth common cause of cancer mortality in Taiwan with high incidence and recurrence and needs new therapeutic strategies. In this study, ursolic acid (UA), ...a triterpenoid, was examined the antitumor potency in OSCC cells. Our results showed that UA inhibited the proliferation of OSCC cells in a dose‐ and time‐dependent manner in both Ca922 and SCC2095 oral cancer cells. UA induced caspase‐dependent apoptosis accompanied with the modulation of various biological biomarkers including downregulating Akt/mTOR/NF‐κB signaling, ERK, and p38. In addition, UA inhibited angiogenesis as evidenced by abrogation of migration/invasion and blocking MMP‐2 secretion in Ca922 cells. Interestingly, UA induced autophagy in OSCC cells, as manifested by LC3B‐II conversion and increased p62 expression and accumulation of autophagosomes. Inhibition by autophagy inhibitor enhanced UA‐mediated apoptosis in Ca922 cells. The experiment provides a rationale for using triterpenoid in the treatment of OSCC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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•Plumbagin does not affect the cell viability of human EPCs.•Plumbagin suppresses VEGF-promoted EPC migration and tube formation.•Plumbagin reduces VEGF-induced promotion of PLC, Akt ...and ERK activation.•Plumbagin inhibits VEGF-induced promotion of NF-κB and HIF-1 activation in EPCs.•Plumbagin suppress EPC expression and angiogenesis in vivo.
Plumbagin, a naturally occurring naphthoquinone component isolated from the root of Plumbago zeylanica, reduces angiogenesis in human umbilical vein endothelial cells; whether plumbagin also has anti-angiogenic activity in human endothelial progenitor cells (EPCs) has remained unclear. Importantly, the recruitment of bone marrow-derived EPCs promotes physiological and pathological neovascularization. In this study, plumbagin inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human EPCs, without cytotoxic effects. We also found that plumbagin inhibited angiogenesis via the phospholipase C (PLC), Akt, extracellular-signal-regulated kinase (ERK), nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 signaling pathways. In an EPC Matrigel plug assay, plumbagin significantly diminished microvessel formation and EPC-specific marker expression. Our report is the first to reveal that plumbagin reduces EPC-related angiogenesis both in vitro and in vivo. Further evaluations of plumbagin are warranted, to determine its antitumor activity and other angiogenesis-related disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Garlic has been used throughout history for both culinary and medicinal purpose. Allicin is a major component of crushed garlic. Although it is sensitive to heat and light and easily metabolized into ...various compounds such as diallyl disulfide, diallyl trisulfide, and diallyl sulfide, allicin is still a major bioactive compound of crushed garlic. The mortality of hepatocellular carcinoma is quite high and ranks among the top 10 cancer-related deaths in Taiwan. Although numerous studies have shown the cancer-preventive properties of garlic and its components, there is no study on the effect of allicin on the growth of human liver cancer cells. In this study, we focused on allicin-induced autophagic cell death in human liver cancer Hep G2 cells. Our results indicated that allicin induced p53-mediated autophagy and inhibited the viability of human hepatocellular carcinoma cell lines. Using Western blotting, we observed that allicin decreased the level of cytoplasmic p53, the PI3K/mTOR signaling pathway, and the level of Bcl-2 and increased the expression of AMPK/TSC2 and Beclin-1 signaling pathways in Hep G2 cells. In addition, the colocalization of LC3-II with MitoTracker-Red (labeling mitochondria), resulting in allicin-induced degradation of mitochondria, could be observed by confocal laser microscopy. In conclusion, allicin of garlic shows great potential as a novel chemopreventive agent for the prevention of liver cancer.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Casticin, a polymethoxyflavone derived from natural plants, has biological activities including induction of cell apoptosis. In this study, we showed the beneficial effects of casticin on the ...inhibition of prostate cancer cell metastasis. Casticin reduced total viable cell number, thus, we selected low doses of casticin for following experiments. Casticin decreased cell mobility, suppressed cell migration and invasion, and reduced cell gelatinolytic activities of MMP‐2/‐9. Furthermore, casticin inhibited the protein levels of AKT, GSK3 αβ, Snail, and MMPs (MMP‐2, ‐9, ‐13, and ‐7) at 24 and 48 hr treatment. Casticin diminished the expressions of NF‐κB p65, GRB2, SOS‐1, MEK, p‐ERK1/2, and p‐JNK1/2 at 48 hr treatment only. However, casticin reduced the level of E‐cadherin at 24 hr treatment but elevated at 48 hr. The novel findings suggest that casticin may represent a new and promising therapeutic agent for the metastatic prostate cancer.
Practical applications
Casticin derived from natural plants had been used for Chinese medicine in Chinese population for thousands of years. In the present study, casticin attenuated metastatic effects, including decreasing viable cell number, inhibiting the migration, invasion, and adhesion, and reducing matrix metalloproteinases activity on human prostate DU 145 cancer cells. In addition, the results also provided possible pathways involved in casticin anti‐metastasis mechanism. We conclude that casticin may be an aptitude anticancer agent or adjuvant for the metastatic prostate cancer in the future.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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