Targeting the hallmarks of cancer

Siddiqa, Aisha; Marciniak, Robert A.

doi:10.4161/cbt.7.5.6163

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…It was reported that Cd is a suspected human hepatic carcinogen and can induce hepatic tumors in rats, 24,29 making the hepatic epithelium a suspect in vivo target of Cd. [33][34][35] In fact, our previous reports have shown that chronic Cd exposure could result in hepatic lesions and transformation. Aberrant DNA methylation of promoter regions may represent one possible mechanism in Cd-induced carcinogenesis.…”

Section: Discussionmentioning

confidence: 98%

Exposure to low dose cadmium enhances FL83B cells proliferation through down-regulation of caspase-8 by DNA hypermethylation

Wang

et al. 2015

Toxicol. Res.

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Cadmium (Cd) is classified as a human carcinogen probably associated with epigenetic change. However, its underlying mechanism and role in epigenetics is still poorly understood. DNA methylation is one of the epigenetic mechanisms by which cells control expression. Our previous in vivo experiment has shown that caspase-8 gene promoter of the rat liver tissue was hypermethylated in Cd at 20 nmol kg −1 for 4 weeks. In the present study, we will disclose whether DNA methylation is also involved in this Cd-stimulated FL83B cell proliferation. When the FL83B cells were exposed to Cd at a low dose (0.085 µM) for only 14 days, cell proliferation and DNMT methyltransferase expression and activity increased, while the mRNA and protein of tumor gene caspase-8 decreased remarkably, along with a significant decrease in cell apoptosis and increase in cell invasion and metastasis. Furthermore, caspase-8 gene promoter in Cd-exposed Fl83B cells was hypermethylated, consistent with our in vivo experiment. A DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), prevented Cd-stimulated cell proliferation, invasion and metastasis associated with recovered caspase-8 expression. These results suggest that low dose Cd may induce caspase-8 gene promoter hypermethylation, resulting in down-regulation of its expression, and consequently promoting cell proliferation, invasion and metastasis and decreasing apoptosis, both of which would contribute to Cd-induced carcinogenesis.

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Section: Discussionmentioning

confidence: 98%

Exposure to low dose cadmium enhances FL83B cells proliferation through down-regulation of caspase-8 by DNA hypermethylation

Wang

et al. 2015

Toxicol. Res.

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“…Molecular-targeted drugs specifically against cancer cells without affecting normal cells are being developed [2]–[4]. Many of the molecular-targeted drugs are inhibitors of proteins involved in signaling transduction, such as growth factors, growth factor receptors or kinases [2], [5].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Apoptosis and FAK Signaling Disruption by a Novel Histone Deacetylase Inhibitor, HTPB, in Antitumor and Antimetastatic Mouse Models

et al. 2012

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BackgroundCompound targeting histone deacetylase (HDAC) represents a new era in molecular cancer therapeutics. However, effective HDAC inhibitors for the treatment of solid tumors remain to be developed.Methodology/Principal FindingsHere, we propose a novel HDAC inhibitor, N-Hydroxy-4-(4-phenylbutyryl-amino) benzamide (HTPB), as a potential chemotherapeutic drug for solid tumors. The HDAC inhibition of HTPB was confirmed using HDAC activity assay. The antiproliferative and anti-migratory mechanisms of HTPB were investigated by cell proliferation, flow cytometry, DNA ladder, caspase activity, Rho activity, F-actin polymerization, and gelatin-zymography for matrix metalloproteinases (MMPs). Mice with tumor xenograft and experimental metastasis model were used to evaluate effects on tumor growth and metastasis. Our results indicated that HTPB was a pan-HDAC inhibitor in suppressing cell viability specifically of lung cancer cells but not of the normal lung cells. Upon HTPB treatment, cell cycle arrest was induced and subsequently led to mitochondria-mediated apoptosis. HTPB disrupted F-actin dynamics via downregulating RhoA activity. Moreover, HTPB inhibited activity of MMP2 and MMP9, reduced integrin-β1/focal adhesion complex formation and decreased pericellular poly-fibronectin assemblies. Finally, intraperitoneal injection or oral administration of HTPB efficiently inhibited A549 xenograft tumor growth in vivo without side effects. HTPB delayed lung metastasis of 4T1 mouse breast cancer cells. Acetylation of histone and non-histone proteins, induction of apoptotic-related proteins and de-phosphorylation of focal adhesion kinase were confirmed in treated mice.Conclusions/SignificanceThese results suggested that intrinsic apoptotic pathway may involve in anti-tumor growth effects of HTPB in lung cancer cells. HTPB significantly suppresses tumor metastasis partly through inhibition of integrin-β1/FAK/MMP/RhoA/F-actin pathways. We have provided convincing preclinical evidence that HTPB is a potent HDAC targeted inhibitor and is thus a promising candidate for lung cancer chemotherapy.

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“…The commitment of cells towards survival or death is determined by the interactions between molecules such as the pro-and anti-apoptotic proteins within the cells. [3] These proteins generally belong to the Bcl-2 family and have a C-terminal hydrophobic sequence that allows the translocation of these proteins to the outer mitochondrial membrane, as well as consist of at least one of four conserved homology BH domains; Bcl-2 homology (BH)1, BH2, BH3 and BH4. [25] Proteins such as Bcl-2, Bcl-extra long (Bcl-xL) and myeloid cell leukaemia-1 (Mcl-1) consist of all four BH domains and act in an anti-apoptotic manner.…”

Section: Key Players Of Apoptosismentioning

confidence: 99%

“…[29] When the balance between pro-apoptosis and antiapoptosis is shifted towards pro-apoptotic molecules, this leads to activation of the caspase cascade, culminating in apoptosis. [3] Thus, caspases are vital components of apoptosis and act as cysteinyl-aspartate (Asp)-proteinases, cleaving substrates downstream of an Asp residue. [5] Caspases are divided into three groups.…”

Section: Key Players Of Apoptosismentioning

confidence: 99%

“…Another imperative characteristic is the ability of cancer cells to escape cell death pathways such as autophagy, necrosis and apoptosis. [3,4] One of these, apoptosis, is regulated by several molecules and consists of two pathways, the extrinsic and intrinsic pathway. Although these two pathways act independently at the beginning, they converge during the activation of the caspase (critical enzymes of apoptosis induction and amplification) cascade.…”

Section: Introductionmentioning

confidence: 99%

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Finding chemo: the search for marine-based pharmaceutical drugs active against cancer

Indumathy

Dass

2013

Journal of Pharmacy and Pharmacology

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Objectives Cancer affects the health of many people globally. The most common treatment that is used for cancer is chemotherapy, which has shown promising results but not without side effects. Some of these side effects jeopardise further treatment, and this eventually leads to advanced stages of malignancy and mortality. As a result, there is a need for better and safer anticancer compounds such as those found naturally. One of the most abundant natural environments to find such compounds is the sea, and this vast resource has been biomined since the 1950s. Key findings There are currently three marine anticancer agents marketed (Yondelis, Cytosar-U and Halaven), with several others undergoing clinical trials. This review discusses marine-derived products in clinical use and in clinical trials, and discusses available literature on the growth suppression or pro-apoptotic properties of these compounds, and the molecular mechanisms underpinning these cell biological phenomena. Summary The marine environment may hold promising anticancer compounds within its depths, warranting further research to be performed in this area, albeit with respect for the natural ecosystems that are being explored for drug discover and subsequently used for drug development.

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Targeting the hallmarks of cancer

Cited by 8 publications

References 20 publications

Exposure to low dose cadmium enhances FL83B cells proliferation through down-regulation of caspase-8 by DNA hypermethylation

Exposure to low dose cadmium enhances FL83B cells proliferation through down-regulation of caspase-8 by DNA hypermethylation

Mitochondrial Apoptosis and FAK Signaling Disruption by a Novel Histone Deacetylase Inhibitor, HTPB, in Antitumor and Antimetastatic Mouse Models

Finding chemo: the search for marine-based pharmaceutical drugs active against cancer

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