Rare Coumarins Induce Apoptosis, G1 Cell Block and Reduce RNA Content in HL60 Cells

AbstractThe rare coumarins stenocarpin, stenocarpin isobutyrate, oficinalin, oficinalin isobutyrate, 8-methoxypeucedanin and the known xanthotoxin, isoimperatorin, bergapten, peucedanin and 8–methoxyisoimperatorin were isolated from Peucedanum luxurians Tamamsch. (Apiaceae) and identified by means of spectral data (1D and 2D NMR). Their immunomodulating activity was evaluated by flow cytometry and their influence on HL60 cells as well as on PHA-stimulated PBLs was tested. All tested coumarins induce apoptosis (maximal in the 48 h culture) and decrease cell proliferation in a time- and dose-dependent manner, especially in HL60 cells. They also induce partial G1 block, but only in HL60 cells (at 100 µM concentrations). Dose-dependent reduction of RNA content was also found in G1 cells treated by the coumarins. All of the tested coumarins also possessed immunomodulatory activities. Bergapten and xanthotoxin were found to be the best candidates for further evaluation as anti-cancer drugs.

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The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

Biochemical Journal ◽

10.1042/bcj20160302 ◽

2016 ◽

Vol 473 (17) ◽

pp. 2635-2643 ◽

Cited By ~ 14

Author(s):

Cristina E. Requena ◽

Guiomar Pérez-Moreno ◽

András Horváth ◽

Beáta G. Vértessy ◽

Luis M. Ruiz-Pérez ◽

...

Keyword(s):

Thymidylate Synthase ◽

Cellular Response ◽

Dna Demethylation ◽

Cancer Drug ◽

Dependent Manner ◽

Strand Breaks ◽

Anti Cancer ◽

Synthase Inhibitor ◽

Dose Dependent ◽

Cytotoxic Mechanism

Decitabine (5-aza-2′-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two ‘house-cleaning’ nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2′-deoxycytidine-5′-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.

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Anti-Cancer Activity of Catechin against A549 Lung Carcinoma Cells by Induction of Cyclin Kinase Inhibitor p21 and Suppression of Cyclin E1 and P–AKT

Applied Sciences ◽

10.3390/app10062065 ◽

2020 ◽

Vol 10 (6) ◽

pp. 2065

Author(s):

Haiyan Sun ◽

Meichen Yin ◽

Danqing Hao ◽

Yixiao Shen

Keyword(s):

Kinase Inhibitor ◽

A549 Cells ◽

Dependent Manner ◽

Cyclin E1 ◽

Lung Carcinoma Cells ◽

Cycle Arrest ◽

Anti Cancer ◽

Berry Fruits ◽

Dose Dependent ◽

Cancer Activity

Catechin is one of the major polyphenols in teas, beans, and berry fruits. A number of studies have confirmed that catechins extract possesses health benefits in the prevention of various chronic diseases. In this study, the anti-cancer activity and mechanism of catechin against non-small cell lung cancer A549 cells were investigated. The inhibitory rate of catechin on the proliferation of A549 cells reached 19.76% at a concentration of 600 μmol·L−1 with 24 h incubation. The results demonstrated that catechin inhibits A549 cells by increasing the expressions of p21 and p27 in the cancer cells. Furthermore, the catechin treatment inhibited the expressions of cyclin E1 and phosphorylation of protein kinase (P–AKT) in a dose-dependent manner, which also contributed to the inhibition of cancer cell proliferation. Therefore, the results of this study indicated that catechin can effectively inhibit the proliferation of A549 cells through regulating its cell cycle arrest or indirectly via the p21 signaling pathway. It would provide important information for developing catechin and catechin-rich functional food or co-therapy for antitumor purposes.

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Comparison of responsiveness to cancer development and anti-cancer drug in three different C57BL/6N stocks

Laboratory Animal Research ◽

10.1186/s42826-019-0015-z ◽

2019 ◽

Vol 35 (1) ◽

Cited By ~ 1

Author(s):

Mi Ju Kang ◽

Ji Eun Kim ◽

Ji Won Park ◽

Hyeon Jun Choi ◽

Su Ji Bae ◽

...

Keyword(s):

Animal Models ◽

Tumor Tissue ◽

Tumor Model ◽

Cancer Drug ◽

Dependent Manner ◽

Cancer Drugs ◽

Ki 67 ◽

Anti Cancer ◽

Dose Dependent ◽

Syngeneic Model

Abstract In our efforts to understand the systemic features of tumors, the importance of animal models is increasing due to the recent growth in the development of immunotherapy and targeted therapies. This has resulted in increased attention towards tumor animal models using C57BL/6N, which are mainly used in immunological studies. In this study, the C57BL/6NKorl stock and two other commercial stocks (C57BL/6NA and C57BL/N6B) are evaluated by comparing the occurrence of tumors using the syngeneic model; furthermore, we compare the response to anti-cancer drugs in the syngeneic model by evaluating survival, growth of tumors, proliferation and molecular biology analysis. In the syngeneic model using LLC (Lewis lung carcinoma) cells, the survival of mice and growth of the tumor showed a better response in the C57BL/6NKorl stock, and was dependent on the cell concentration of the dosing tumor, as compared to the other C57BL/6N stocks. However, the Ki-67 staining showed only little difference in cell proliferation within the tumor tissue each mouse stocks. Comparing the sensitivity to anti-cancer drug by examining changes in growth, volume and weight revealed that cisplatin treatment for tumor-bearing C57BL/6NKorl was more dependent on concentration. The Ki-67 staining, however, showed no difference among the C57BL/6N stocks after cisplatin treatment. The expressions of p27 and p53 tumor suppressor proteins, caspase-3 and Bax showed dose-dependent increase after exposure to cisplatin, whereas the expression of Bcl-2 was reduced in a dose-dependent manner. Furthermore, the expressions of MMP-2 and VEGF involved in metastasis, as well as inflammatory genes IL-1β, IL-6 and IL-10, showed dose-dependent decrease in tumor tissue after cisplatin exposure. Differences observed among the C57BL/6N stocks were not significant. Taken together, our studies reveal that C57BL/6NKorl has the potential of being a useful biological resource established in Korea, as it does not differ from the two commercially available C57BL/6N stocks when considering response to tumor generation and sensitivity to anti-cancer drugs using the syngeneic tumor model.

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Insights Into the Mechanism of Zymogen Protein C Protection Against Cancer Progression

Blood ◽

10.1182/blood.v120.21.3350.3350 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3350-3350 ◽

Cited By ~ 1

Author(s):

Julie M Crudele ◽

Geerte L. Van Sluis ◽

Paris Margaritis ◽

Joshua I Siner ◽

Michael Sliozberg ◽

...

Keyword(s):

Cancer Treatment ◽

Tumor Progression ◽

Cancer Progression ◽

Protein C ◽

Metastatic Cancer ◽

Dependent Manner ◽

B16f10 Cells ◽

Anti Cancer ◽

Anticoagulant Function ◽

Dose Dependent

Abstract Abstract 3350 Cancer is frequently associated with activation of coagulation, and a procoagulant state facilitates tumor metastasis. Recent studies have suggested that the activated protein C (aPC) pathway plays a role in modulating tumor metastasis, and this protection likely requires both the anticoagulant and cytoprotective effects of aPC. Notably, our early work revealed that the inactive precursor, zymogen PC (zyPC), can even more effectively protect against metastasis. The aim of this study was therefore to explore mechanisms through which zyPC could prevent metastatic cancer progression in a murine cancer model. A liver gene transfer model using viral vectors was utilized to achieve a wide range of sustained expression of wildtype (WT) or mutant murine zyPCs. C57BL/6 experimental mice expressing stable levels of zyPCs and age and gender matched control mice receiving PBS were injected intravenously with 2.5×105 murine melanoma B16F10 cells, which metastasize to the lungs. After 3 weeks the number of pulmonary tumors was determined. Expression of WT zyPC in C57BL/6s decreased the rates of metastasis in a dose-dependent manner compared to PBS controls (p<0.01; n=8–18/group). These effects were noted even in mice injected with low vector dose (200% zyPC expression). Conversely, when PC-deficient mice (3% of normal, n=7) were administered B16F10s without zyPC-expression, they did not survive the full 3 weeks, while their littermate controls (PC > 50% of normal, n=6) did despite high rates of metastasis. These data clearly demonstrate the protective role of zyPC in tumor progression. We then tested modified zyPCs to identify the critical functions responsible for our observations in this tumor model. Two mutants with minimal anticoagulant function, R15Q and S195A, were generated. zyPC-R15Q is unable to dock to the thrombin-thrombomodulin complex active site and so cannot be converted to aPC. Compared to PBS controls (n=7), mice expressing zyPC-R15Q still showed a significant decrease in the number of tumor foci (p<0.001; 75–99% reduction; n=13) similar to the WT zyPC (p=0.28; n=8). Mice expressing zyPC-S195A (n=12), which has a mutation in the serine protease active site, also showed a significant decrease in the number of tumor foci compared to PBS controls (n=8; p<0.05; 90–99% reduction). As with the R15Q, mutating the S195 did not affect the ability of zyPC to protect against metastasis (p=0.22). Next, we tested the importance of the main PC/aPC cellular receptors in our model. Binding to endothelial protein C receptor (EPCR) enhances activation of PC. We inhibited this binding by injecting anti-EPCR blocking antibody 1560 (J Thromb Haemost. 2005 3:1351) intraperitoneally one hour prior to the B16F10 cells. zyPC-expressing mice that received anti-EPCR antibody (n=22) still had a significant reduction in tumor rates compared to PBS controls (n=10; p<0.01; 45–75% reduction). Moreover, mice expressing zyPC had similar levels of protection whether they received the anti-EPCR antibody or an isotype control (n=22–24; p=0.31). EPCR binding not only increases activation of PC, it also mediates the cytoprotective effect by clustering with and facilitating the activation of the signaling protease-activated receptor 1 (PAR1). PAR1 −/− mice expressing zyPC (n=21) challenged with B16F10 cells still had reduced rates of metastasis compared to PAR1 −/− PBS controls (n=15; p<0.01; 67% reduction). The zyPC protection in PAR1 null mice was comparable to that in PAR1 +/− littermate controls (n=10; p=0.619). Collectively, these findings suggest a distinct mechanism by which zyPC modulates tumor progression independent of EPCR and PAR1, both of which are required for aPC-mediated protection. Despite elevated circulating levels of PC, zyPC-expressing mice did not suffer from increased blood loss following tail clipping or show prolonged activated partial thromboplastin times (aPTTs) compared to hemostatically normal mice. In conclusion, zyPC protects against metastatic cancer progression in a dose-dependent manner. Our data show for the first time that this zyPC effect is independent of its anticoagulant function. Furthermore, protection is not mediated through EPCR or PAR1, suggesting an alternative pathway by which zyPC limits tumor progression. These findings suggest that WT zyPC and variants with little to no anticoagulant function are safe and efficacious in preventing metastatic cancer progression. Disclosures: Van Sluis: PCT patent pending: Protein C: A Zymogen for Anti-Cancer Treatment Patents & Royalties. High:PCT patent pending: Protein C: A Zymogen for Anti-Cancer Treatment Patents & Royalties. Spek:PCT patent pending: Protein C: A Zymogen for Anti-Cancer Treatment Patents & Royalties. Arruda:PCT patent pending: Protein C: A Zymogen for Anti-Cancer Treatment Patents & Royalties.

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Anti-proliferative Activities of Two Flavonols with Unsubstituted B-ring from the Leaves of Platanus acerifolia

Natural Product Communications ◽

10.1177/1934578x1701201110 ◽

2017 ◽

Vol 12 (11) ◽

pp. 1934578X1701201

Author(s):

Hui-Feng Chen ◽

Ri-Zhen Huang ◽

Bo Zuo ◽

Lan-Ju Ji ◽

Zhi-Jian Mo ◽

...

Keyword(s):

Ethanol Extract ◽

Positive Control ◽

Control Group ◽

Dependent Manner ◽

Hoechst 33258 ◽

Caspase 9 ◽

Platanus Acerifolia ◽

Anti Cancer ◽

Cellular Apoptosis ◽

Dose Dependent

The anti-proliferative activities against five cancer cell lines of two flavonols (1, 2) with unsubstituted B ring isolated from the ethanol extract of the leaves of Platanus acerifolia were investigated. The results showed that compound 1 possessed a noteworthy anti-proliferative activity against MGC-803 cells with an IC50 value of 17.26±1.04 μM, and compound 2 was less active than 1 with an IC50 value of 20.29±1.37 μM compared with 41.94±1.58 μM for the positive control group. In addition, the results of Hoechst 33258 staining, AO/EB staining and annexinV-FITC assays indicated that 1 caused a significant MGC-803 cellular apoptosis in a dose-dependent manner. The further mechanisms showed that compound 1 induced the production of ROS, decreased the mitochondrial membrane potential, and altered pro- and anti-apoptotic proteins, leading to activation of caspase-9 and caspase-3 in the process of cellular apoptosis. The present investigation indicated that compound 1 could be used as a potential anti-cancer candidate.

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Evaluation of in Vitro Bio-Activities Effects of WST (Wushanshencha)

Applied Sciences ◽

10.3390/app9071325 ◽

2019 ◽

Vol 9 (7) ◽

pp. 1325 ◽

Cited By ~ 5

Author(s):

Chong Li ◽

Chaomin Liu ◽

Jing Zhang ◽

Honggang Li ◽

Yan Zhou ◽

...

Keyword(s):

Hepg2 Cells ◽

Mutagenic Effect ◽

High Dose ◽

Dependent Manner ◽

Human Hepatoma Cells ◽

Related Factors ◽

Anti Cancer ◽

Functional Components ◽

Dose Dependent

As a traditional Chinese drink, tea is favored for its rich flavor and its medicinal functionality. In this study, the in vitro bioactivities of Wushanshencha (WST; a local tea from Chongqing, China), which is processed mainly from the leaves of the wild Malus hupehensis (Pamp.) Rehd.). We assessed the scavenging capacity of tea extracts on 1, 1-diphenyl-2-picrylhydrazyl (DPPH); 2, 2′-azino-bis (3-ethylbenzthiazoline-6- sulphonic acid) diammonium salt (ABTS); and hydroxyl (OH) free radicals, and demonstrate the high antioxidant activity and dose-dependent relationship of these extracts. We also detail the anti-mutagenic effect of these tea extracts against the Salmonella typhimurium TA98 strain induced by the 2, 7-diaminofluorene (2, 7-AF) mutagen and the TA100 strain induced by the N-methyl-N′-nitro- N- nitrosoguanidine (MNNG) mutagen at concentrations of 1.25 and 2.50 mg/plate, respectively, with the high-dose groups showing better results. We investigated the anticancer mechanisms of WST extracts (40, 100, and 160 μg/mL) in HepG2 human hepatoma cells via 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR). The results showed that the proliferation of HepG2 cells was significantly inhibited in a dose-dependent manner by the tea extracts. Moreover, apoptosis in HepG2 cells was induced via upregulation of Caspase-3, Caspase-7, Caspase-8, Caspase-9, p21, p53, and Bax as well as downregulation of Bcl-2 apoptosis-associated factors, as assessed via mRNA expression levels after treating with WST extracts. The expression of inflammation-related factors, e.g., NF-κB, and Cox-2, was significantly downregulated by the WST extracts, demonstrating its inflammatory properties. Together, these observations indicated that WST extracts have anti-inflammatory and anti-cancer properties. In addition, high-performance liquid chromatography (HPLC) analysis showed that WST extracts contained chlorogenic acid, 4-hydroxycinnamic acid, isoquercitrin, taxifolin, quercitrin, rosmarinic acid, myricetin, baicalin, neosperidin dihydrochalcone, and quercetin. As such, WST appears to be an effectively functional drink, due to its rich functional components and anti-cancer activity.

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Zoledronic acid induces anti-cancer effects on prostate cancer cells through the modulation of the angiogenesis associated CYR61 and the androgen-differentiation associated NDRG-1 genes

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21079 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21079-21079

Author(s):

G. Tonini ◽

B. Vincenzi ◽

M. Marra ◽

A. Baldi ◽

S. Addeo ◽

...

Keyword(s):

Prostate Cancer ◽

Zoledronic Acid ◽

The Other ◽

Cytotoxic Agents ◽

Dependent Manner ◽

Other Hand ◽

Anti Cancer ◽

Pc3 Cells ◽

Upregulated Genes ◽

Dose Dependent

21079 Background: Aminobisphosphonates (ABPs) has a definite direct anti-tumour activity but a limited activity in vivo. Their molecular targets are still not completely defined. Therefore, we have studied the effects of zoledronic acid (ZOL) addition to prostate cancer PC3 cells on gene expression profile. Methods: We have treated PC3 cells with 100 μM ZOL for 24 hours, extracted mRNAs and probed on Affimetrix HG-U133. Thereafter, we have identified down modulated and upregulated genes and checked for modulation of mRNA with RT PCR and of the relative encoded proteins with western blotting. Results: We have found 6 down modulated and 32 upregulated genes. We have focused our attention on NDRG1 associated to the androgen-differentiation and on Cysteine rich 61 (CYR61) involved in the regulation of proliferation and angiogenesis. NDRG1 mRNA was up-regulated and CYR61 mRNA was downregulated by ZOL in a dose-dependent manner. Similar effects were observed at protein product levels with an about 2-fold change recorded already in cells treated with 50 μM ZOL. Interestingly, also Gefitinib, Sorafenib and Tipifarnib used at their IC:50s could induce changes in both NDRG1 and CYR61 expression, but 50 μM ZOL was about 2-fold more potent. On the other hand, cytotoxic agents such as docetaxel did not have any effect. The addition of farnesol (FOH) or geranylgeraniol (GGOH) to ZOL-treated cells was able to counteract the effect of ZOL on CYR61 expression partially or completely, respectively. On the other hand, both FOH and GGOH had poor effect on the regulation of NDRG1 expression induced by ZOL. Conclusions: ZOL induces a strong regulation of the expression of NDRG1 and CYR61 at both mRNA and protein levels that appears to be dose-dependent and specific. CYR61 modulation seems to be more dependent from the inhibition of geranylgeranylation processes while NDRG1 changes could be at least in part independent from the inhibition of isoprenylation induced by ZOL. The study of the biological relevance of these effects on the anti-cancer effects of ZOL is ongoing with small interference RNA approaches. No significant financial relationships to disclose.

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A Neuroinflammation Inhibitor, Hypoxylon xanthone A, from Soil Fungus Hypoxylon sp.

Letters in Organic Chemistry ◽

10.2174/1570178616666191023100252 ◽

2020 ◽

Vol 17 (2) ◽

pp. 116-120

Author(s):

Ying Xiao ◽

Bing Xu ◽

You Kang ◽

Yuedi Li ◽

Yong Cui ◽

...

Keyword(s):

Ethyl Acetate ◽

Nmr Spectra ◽

Soil Fungus ◽

2D Nmr ◽

Inhibitory Effect ◽

No Production ◽

Dependent Manner ◽

Solid Culture ◽

2D Nmr Spectra ◽

Dose Dependent

: Hypoxylon sp. was used to ferment at 25°C for 45 days. The solid culture of Hypoxylon sp. was extracted with 75% EtOH under ultrasonic for twice. And the dried combined extracts were then suspended in H2O and partitioned with ethyl acetate. EtOAc extracts were subjected to a silica gel column and eluted with petroleum ether - acetone to a.ord seven fractions. Sephadex LH-20 and RPHPLC were used subsequently to yield a novel xanthone metabolite (Hypoxylon xanthone A). Its structure was elucidated based on HR-ESI-MS, 1D-, 2D-NMR spectra, and the comparison of the experimental and calculated ECD spectra. The anti-neuroinflammatory assay of Hypoxylon xanthone A, as manifested by the inhibitory effect on LPS-induced NO production in BV-2 microglial cells, indicated almost the same inhibitory effect as minocycline in a dose-dependent manner within the concentration of 1-50 μM, suggesting that Hypoxylon xanthone A could be a new potential neuroinflammation inhibitor.

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Sanguinarine Mediated Anti-Tumor activity Via Targeting JAK/STAT3 Pathway in Thyroid Cancer

University of the Future: Re-Imagining Research and Higher Education ◽

10.29117/quarfe.2020.0155 ◽

2020 ◽

Author(s):

Elham Ahmed ◽

Abdul Khan ◽

Kirti S. Prabhu ◽

Kodappully Siveen ◽

Zafar Nawaz ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Lines ◽

Caspase 3 ◽

Therapeutic Potential ◽

Dependent Manner ◽

Pharmacological Activities ◽

Anti Cancer ◽

Anti Tumor Activity ◽

Dose Dependent ◽

Inhibit Cell Proliferation

Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. This research aimed to investigate the antiproliferative and anti-cancer potential of SNG against two well characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1 .In both cell lines , SNG was able to inhibit cell proliferation in time and dose dependent manner. Western blot analysis revealed increased expression of apoptosis and autophagy markers , caspase-3,cleaved caspase-3 , P62, and LC3. SNG modulate its anticancer effect through ROS production, because NAC was able to reverse SNG effect. Interestingly, co-treatment of PTC with SNG and cisplatin amplified anticancer activity. Finally, SNG treatment of PTC spheroid suppressed its growth with downregulation of stemness markers including ALDH2 and SOX2 markers. In conclusion, SNG enhanced the anti cancer activity against PTC cells and the effect is amplified when cisplatin is added.

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Tea polyphenol decreased growth and invasion in human ovarian cancer cells

European Journal of Inflammation ◽

10.1177/1721727x16674480 ◽

2016 ◽

Vol 14 (3) ◽

pp. 206-211

Author(s):

Qin Huang ◽

Ting Du ◽

Qiu-Xia Qu

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Therapeutic Strategy ◽

Ovarian Cancer Cells ◽

Cyclin D ◽

Dependent Manner ◽

Tea Polyphenol ◽

Anti Cancer ◽

Dose Dependent

Tea polyphenols (TP) are functional substances present in tea, which is one of the most promising preventive agents for cancer. This study was carried out to analyze the effects of TP on the ovarian cancer cells and possible mechanisms involved. TP led to inhibition of cell growth in a time- and dose-dependent manner, and promoted entry into the apoptosis-phase of the cell cycle. TP also decreased the invasion of ovarian cancer cells in vitro. In addition, TP treatment upregulated the mRNA expressions rate of Bax/Bcl-2 and downregulated Cyclin D and MMP2 mRNA expressions. Taken together, our data highlight that TP could be a potential therapeutic strategy for ovarian cancer. These findings also suggested that oncogens are involved in the anti-cancer effects of TP.

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