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Journal ArticleDOI

Menadione (Vitamin K3) Induces Apoptosis of Human Oral Cancer Cells and Reduces their Metastatic Potential by Modulating the Expression of Epithelial to Mesenchymal Transition Markers and Inhibiting Migration

30 Sep 2013-Asian Pacific Journal of Cancer Prevention (Asian Pac J Cancer Prev)-Vol. 14, Iss: 9, pp 5461-5465

TL;DR: The results show that menadione is more cytotoxic to SAS (oral squamous carcinoma) cells but not to non-tumorigenic HEK293 and HaCaT cells, and reveal and confirm that mendione is a potential candidate in oral cancer therapy as it exhibits cytotoxicity, antineoplastic and antimigratory effects besides effectively blocking EMT in oralcancer cells.
Abstract: Oral cancer is one of the most commonly occurring cancers worldwide, decreasing the patient’s survival rate due to tumor recurrence and metastasis. Menadione (Vitamin K3) is known to exhibit cytotoxicity in various cancer cells but the present study focused on its effects on viability, apoptosis, epithelial to mesenchymal transition (EMT), anchorage independent growth and migration of oral cancer cells. The results show that menadione is more cytotoxic to SAS (oral squamous carcinoma) cells but not to non-tumorigenic HEK293 and HaCaT cells. Menadione treatment increased the expression of pro-apoptotic proteins, Bax and p53, with a concurrent decrease in anti-apoptotic proteins, Bcl-2 and p65. Menadione induced the expression of E-cadherin but reduced the expression of EMT markers, vimentin and fibronectin. Menadione also inhibited anchorage independent growth and migration in SAS cells. These findings reveal and confirm that menadione is a potential candidate in oral cancer therapy as it exhibits cytotoxic, antineoplastic and antimigratory effects besides effectively blocking EMT in oral cancer cells.
Topics: Menadione (62%), Epithelial–mesenchymal transition (57%), Cancer cell (56%), Squamous carcinoma (56%), Cancer (53%)
Citations
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Journal ArticleDOI
Chenbo Ding1, Xiaobo Fan1, Guoqiu Wu1Institutions (1)
TL;DR: The structure, effector functions of PRDX1, its role in cancer and the pivotal role of ROS in anticancer treatment are reviewed.
Abstract: Peroxiredoxins (PRDXs), a ubiquitous family of redox-regulating proteins, are reported of potential to eliminate various reactive oxygen species (ROS). As a major member of the antioxidant enzymes, PRDX1 can become easily over-oxidized on its catalytically active cysteine induced by a variety of stimuli in vitro and in vivo. In nucleus, oligomeric PRDX1 directly associates with p53 or transcription factors such as c-Myc, NF-κB and AR, and thus affects their bioactivities upon gene regulation, which in turn induces or suppresses cell death. Additionally, PRDX1 in cytoplasm has anti-apoptotic potential through direct or indirect interactions with several ROS-dependent (redox regulation) effectors, including ASK1, p66Shc , GSTpi/JNK and c-Abl kinase. PRDX1 is proven to be a versatile molecule regulating cell growth, differentiation and apoptosis. Recent studies have found that PRDX1 and/or PRDX1-regulated ROS-dependent signalling pathways play an important role in the progression and metastasis of human tumours, particularly in breast, oesophageal and lung cancers. In this paper, we review the structure, effector functions of PRDX1, its role in cancer and the pivotal role of ROS in anticancer treatment.

90 citations


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TL;DR: NFFinder is presented, a bioinformatics tool for identifying potential useful drugs in the context of orphan diseases that uses transcriptomic data to find relationships between drugs, diseases and a phenotype of interest, as well as identifying experts having published on that domain.
Abstract: Drug repositioning, using known drugs for treating conditions different from those the drug was originally designed to treat, is an important drug discovery tool that allows for a faster and cheaper development process by using drugs that are already approved or in an advanced trial stage for another purpose. This is especially relevant for orphan diseases because they affect too few people to make drug research de novo economically viable. In this paper we present NFFinder, a bioinformatics tool for identifying potential useful drugs in the context of orphan diseases. NFFinder uses transcriptomic data to find relationships between drugs, diseases and a phenotype of interest, as well as identifying experts having published on that domain. The application shows in a dashboard a series of graphics and tables designed to help researchers formulate repositioning hypotheses and identify potential biological relationships between drugs and diseases. NFFinder is freely available at http://nffinder.cnb.csic.es.

44 citations


Journal ArticleDOI
Thacker Pooja1, Devarajan Karunagaran1Institutions (1)
TL;DR: Emodin significantly down regulated the expression of key players of Wnt signaling and also that of its various downstream targets and may provide important insights for the use of this anthraquinone as a potential complementary and integrated medicine for the treatment of human colorectal cancer.
Abstract: Wnt signaling is involved in the regulation of cell proliferation, differentiation and apoptosis. Its aberrant activation is a key event in the pathogenesis and progression of human colorectal cancers. Dietary phytochemicals are gaining importance as chemotherapeutic agents owing to their potential to prevent, delay or reverse oncogenesis. Here we demonstrate that emodin (1,3,8-trihydroxy-6-methylanthraquinone), an anthraquinone present in the roots and bark of several medicinal plants, down regulates Wnt signaling pathway in human colorectal cancer cells (SW480 and SW620) by down regulating TCF/LEF transcriptional activity. Emodin significantly down regulated the expression of key players of Wnt signaling (β-catenin and TCF7L2) and also that of its various downstream targets (cyclin D1, c-Myc, snail, vimentin, MMP-2 and MMP-9). Two novel targets of emodin׳s action were discovered namely Wnt co-activator p300 (down regulated) and repressor HBP1 (up regulated). Morphological changes induced by emodin suggest mesenchymal to epithelial transition accompanied by the increase in E-cadherin expression in human colorectal cancer cells but a differentiation marker (alkaline phosphatase) was activated only in SW620 cells (metastatic origin) and not in SW480 cells (primary tumor-derived). Moreover, our data indicate that reactive oxygen species plays a key role in emodin-mediated down regulation of Wnt signaling as emodin-mediated inhibition of migration and induction of growth arrest were partially rescued by the reactive oxygen species scavenger ascorbic acid. Effects of emodin shown in this study may provide important insights for the use of this anthraquinone as a potential complementary and integrated medicine for the treatment of human colorectal cancer.

43 citations


Cites methods from "Menadione (Vitamin K3) Induces Apop..."

  • ...…diamine tetra acetic acid, 1 mM β-glycerophosphate,1% Triton X 100, 2.5 mM sodium pyrophosphate, 1 mM sodium orthovanadate, 0.5% sodium deoxycholate, 1 mM phenyl methane sulfonyl fluoride, 20 mM sodium fluoride, 1% protease inhibitor], incubated for 1 h, and centrifuged (Suresh et al., 2013)....

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  • ...5% sodium deoxycholate, 1 mM phenyl methane sulfonyl fluoride, 20 mM sodium fluoride, 1% protease inhibitor], incubated for 1 h, and centrifuged (Suresh et al., 2013)....

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Journal ArticleDOI
Zengenni Liang1, Yu-Tong Guo, You-Jin Yi, Ren-Cai Wang  +2 moreInstitutions (1)
TL;DR: It is demonstrated for the first time that GLP shows prominent anticancer activities against the HCT-116 human colon cancer cell line through triggering intracellular calcium release and the death receptor pathway.
Abstract: Ganoderma lucidum polysaccharides (GLP) extracted from Ganoderma lucidum have been shown to induce cell death in some kinds of cancer cells. This study investigated the cytotoxic and apoptotic effect of GLP on HCT-116 human colon cancer cells and the molecular mechanisms involved. Cell proliferation, cell migration, lactate dehydrogenase (LDH) levels and intracellular free calcium levels ([Ca 2+ ]i) were determined by MTT, wound-healing, LDH release and fluorescence assays, respectively. Cell apoptosis was observed by scanning and transmission electron microscopy. For the mechanism studies, caspase-8 activation, and Fas and caspase-3 expression were evaluated. Treatment of HCT-116 cells with various concentrations of GLP (0.625-5 mg/mL) resulted in a significant decrease in cell viability ( P< 0.01). This study showed that the antitumor activity of GLP was related to cell migration inhibition, cell morphology changes, intracellular Ca 2+ elevation and LDH release. Also, increase in the levels of caspase-8 activity was involved in GLP-induced apoptosis. Western blotting indicated that Fas and caspase-3 protein expression was up-regulated after exposure to GLP. This investigation demonstrated for the first time that GLP shows prominent anticancer activities against the HCT-116 human colon cancer cell line through triggering intracellular calcium release and the death receptor pathway.

33 citations


Additional excerpts

  • ...The signal was detected as described (Suresh et al., 2013)....

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Journal ArticleDOI
TL;DR: This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1.
Abstract: Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.

30 citations


Cites background from "Menadione (Vitamin K3) Induces Apop..."

  • ...providing evidence for use of quinones in anticancer therapies [52, 53]....

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References
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Journal ArticleDOI
Chun Chi Liang1, Ann Y. Park1, Jun-Lin Guan1Institutions (1)
TL;DR: The in vitro scratch assay is particularly suitable for studies on the effects of cell–matrix and cell–cell interactions on cell migration, mimic cell migration during wound healing in vivo and are compatible with imaging of live cells during migration to monitor intracellular events if desired.
Abstract: In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro

3,274 citations


Journal ArticleDOI
TL;DR: Clonogenic assay or colony formation assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony that can be used to determine cell reproductive death after treatment with ionizing radiation and the effectiveness of other cytotoxic agents.
Abstract: Clonogenic assay or colony formation assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony. The colony is defined to consist of at least 50 cells. The assay essentially tests every cell in the population for its ability to undergo "unlimited" division. Clonogenic assay is the method of choice to determine cell reproductive death after treatment with ionizing radiation, but can also be used to determine the effectiveness of other cytotoxic agents. Only a fraction of seeded cells retains the capacity to produce colonies. Before or after treatment, cells are seeded out in appropriate dilutions to form colonies in 1-3 weeks. Colonies are fixed with glutaraldehyde (6.0% v/v), stained with crystal violet (0.5% w/v) and counted using a stereomicroscope. A method for the analysis of radiation dose-survival curves is included.

2,700 citations


"Menadione (Vitamin K3) Induces Apop..." refers background in this paper

  • ...…colony formation and migration of SAS cells Anchorage independent growth of cells in soft agar is one of the hallmark characteristics of cellular transformation and uncontrolled cell growth, with normal cells typically being incapable of growing in semisolid matrices (Franken et al., 2006)....

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TL;DR: There have been important advances in understanding of the molecular pathogenesis and progression of head and neck cancer and also in approaches to therapy, which include innovations in surgery, radiation therapy, and cytotoxic-drug therapy.
Abstract: Head and neck cancers include neoplasms of the oral cavity, pharynx, and larynx. The risk of these cancers is strongly associated with smoking and alcohol ingestion. There have been important advances in understanding of the molecular pathogenesis and progression of head and neck cancer and also in approaches to therapy, which include innovations in surgery, radiation therapy, and cytotoxic-drug therapy.

1,211 citations


Journal ArticleDOI
Abstract: A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.

728 citations


"Menadione (Vitamin K3) Induces Apop..." refers background in this paper

  • ...In addition to these properties, EMT confers drug resistance to lung cancer (Nurwidya et al., 2012) and pancreatic cancer (Arumugam et al., 2009) cells....

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Abstract: Carcinogenesis involves the accretion of unprogrammed genetic and epigenetic changes, which lead to dysregulation of the normal control of cell number. But a key clinical turning point in carcinoma progression is the establishment by emigrant cells of secondary growth sites (i.e., metastasis). The

634 citations


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