Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the HER2/neu oncogene (also known as c-erbB2) is a frequent molecular event in multiple human cancers, including breast and ovarian cancer. Patients with cancer that overexpress HER2/neu are associated with unfavorable prognosis, shorter relapse time, and low survival rate. Treatments that target HER2/neu expression in cancer cells have been shown to be useful strategies to significantly reverse the malignancy induced by HER2/neu overexpression. The humanized anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) has proven to be effective in clinical trials in patients with metastatic breast cancer. In addition, tyrosine kinase inhibitors such as emodin can also target the HER2/neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-overexpressing breast cancer cells. Emodin also sensitizes HER2/neu-overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene. We have identified a number of potent transcriptional regulators, including the ets family member PEA3 and the adenovirus type 5 E1A, which are able to repress HER2/neu gene expression. Expression of these transcriptional regulators resulted in downregulation of HER2/neu promoter activity and reversed the transformed phenotype of the cancer cells in vitro. In vivo studies show that these HER2/neu repressors can act therapeutically as tumor suppressor genes for tumors that overexpress HER2/neu. These preclinical studies clearly indicate that transcriptional repressors that downregulate HER2/neu can be effective regimens for cancer treatment in a gene therapy format. More importantly, the tumor-free survival rate of treated animals is dramatically increased under nontoxic doses compared with untreated animals. A phase I clinical trial using E1A-liposome in breast and ovarian patients has recently been completed. Following treatment, we observed downregulation of the HER2/neu protein accompanied by E1A expression in both cancer and noncancer cells. Numbers of tumor cells in the pleural effusion or ascites were found to be dramatically reduced after treatment. Furthermore, apoptosis was strongly induced in the tumor cells. A phase II study has been started to further evaluate therapeutic efficacy and tumor suppression mechanisms of E1A. These studies show the clinical potential of targeting HER2/neu in cancer therapy.
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PMID:Targeting HER2: recent developments and future directions for breast cancer patients. 1177 2

Previous experiments have shown that emodin is highly active in suppressing the proliferation of several tumor cell lines. However, it is not clear that emodin can induce growth inhibition of hepatoma cells. We have found that emodin induces apoptotic responses in the human hepatocellular carcinoma cell lines (HCC) Mahlavu, PLC/PRF/5 and HepG2. The addition of emodin to these three cell lines led to inhibition of growth in a time- and dose-dependent manner. Emodin generated reactive oxygen species (ROS) in these cells which brought about a reduction of the intracellular mitochondrial transmembrane potential (DeltaPsim), followed by the activation of caspase-9 and caspase-3, leading to DNA fragmentation and apoptosis. Our findings demonstrate that ROS and the resulting oxidative stress play a pivotal role in apoptosis. Preincubation of hepatoma cell lines with the hydrogen peroxide-scavenging enzyme, catalase (CAT) and cyclosporin A (CsA), partially inhibited apoptosis. These results demonstrate that enhancement of generation of ROS, DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin.
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PMID:Induction of apoptosis in hepatocellular carcinoma cell lines by emodin. 1271 64

Although arsenic trioxide (As(2)O(3)) induces apoptosis in a relatively wide spectrum of tumors, the sensitivity of different cell types to this treatment varies to a great extent. Because reactive oxygen species (ROS) are critically involved in As(2)O(3)-induced apoptosis, we attempted to explore the possibility that elevating the cellular ROS level might be an approach to facilitate As(2)O(3)-induced apoptosis. Emodin, a natural anthraquinone derivative, was selected because its semiquinone structure is likely to increase the generation of intracellular ROS. Its independent and synergistic effects with As(2)O(3) in cytotoxicity were studied, and the plausible signaling mechanism was investigated in HeLa cells. Cell Proliferation Assay and flow cytometry were used to assess cell viability and apoptosis. Electrophoretic mobility shift assay, luciferase reporter assay, and Western blotting were performed to analyze signaling alteration. The results demonstrated that coadministration of emodin, at low doses of 0.5-10 micro M, with As(2)O(3) enhanced As(2)O(3)-rendered cytotoxicity on tumor cells, whereas these treatments caused no detectable proproliferative or proapoptotic effects on nontumor cells. ROS generation was increased, and activation of nuclear factor kappaB and activator protein 1 was suppressed by coadministration. All enhancements by emodin could be abolished by the antioxidant N-acetyl-L-cysteine. Therefore, we concluded that emodin sensitized HeLa cells to As(2)O(3) via generation of ROS and ROS-mediated inhibition on two major prosurvival transcription factors, nuclear factor kappaB and activator protein 1. This result allows us to propose a novel strategy in chemotherapy that uses mild ROS generators to facilitate apoptosis-inducing drugs whose efficacy depends on ROS.
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PMID:Emodin enhances arsenic trioxide-induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling. 1472 14

Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been reported to exhibit anti-cancer effect on several human cancers such as liver cancers and lung cancers. However, the molecular mechanisms of emodin-mediated tumor regression have not been fully defined. In this study, we show that treatment with 50 microM emodin resulted in a pronounced release of cytochrome c, activation of caspase-2, -3, and -9, and apoptosis in human lung adenocarcinoma A549 cells. These events were accompanied by the inactivation of ERK and AKT, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential ((Delta)psi(m)), decrease of mitochondrial Bcl-2, and increase of mitochondrial Bax content. Ectopic expression of Bcl-2, or treatment with aurintricarboxylic acid, furosemide or caspase inhibitors markedly blocked emodin-induced apoptosis. Conversely, pharmacologic ERK and AKT inhibition promoted emodin-induced apoptosis. Furthermore, the free radical scavenger ascorbic acid and N-acetylcysteine attenuated emodin-mediated ROS production, ERK and AKT inactivation, mitochondrial dysfunction, Bcl-2/Bax modulation, and apoptosis. Take together, these findings suggest that in A549 cells, emodin-mediated oxidative injury acts as an early and upstream change in the cell death cascade to antagonize cytoprotective ERK and AKT signaling, triggers mitochondrial dysfunction, Bcl-2 and Bax modulation, mitochondrial cytochrome c release, caspase activation, and consequent leading to apoptosis.
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PMID:Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. 1594 63

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) could enhance the sensitivity of tumor cells to arsenic trioxide (As2O3)-induced apoptosis via generation of ROS, but the molecular mechanism has not been elucidated. Here, we carried out cDNA microarray-based global transcription profiling of HeLa cells in response to As2O3/emodin cotreatment, comparing with As2O3-only treatment. The results showed that the expression of a number of genes was substantially altered at two time points. These genes are involved in different aspects of cell function. In addition to redox regulation and apoptosis, ROS affect genes encoding proteins associated with cell signaling, organelle functions, cell cycle, cytoskeleton, etc. These data suggest that based on the cytotoxicity of As2O3, emodin mobilize every genomic resource through which the As2O3-induced apoptosis is facilitated.
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PMID:Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. 1604 14

Invasion of tumor cells into the surrounding normal brain tissues is a prominent feature of malignant gliomas. Malignant glioma cells secrete thrombospondin-1 which participates in the motility of glioma cells and binds cell surface heparan sulfate proteoglycan. To clarify the invasion mechanism of tumor cells, expression of the syndecans (syndecan-1, -2, -3, and -4), a major cell surface heparan sulfate proteoglycan family, was analyzed in malignant gliomas. Involvement of nuclear factor-kappaB (NF-kappaB) on syndecan-1 expression was also investigated. Using reverse transcription-PCR, the authors analyzed the expression of syndecan-1, -2, -3, and -4 in 10 malignant glioma cell lines, 2 glioblastoma specimens, and 2 normal brain specimens. All malignant glioma cell lines and glioblastoma specimens expressed all types of syndecan mRNA, except in one glioma cell line that lacked syndecan-3 expression. On the other hand, normal brain specimens expressed syndecan-2, -3, and -4 mRNA, but did not syndecan-1 mRNA. Syndecan-1 protein was localized in the cell surface of all malignant glioma cell lines by flow cytometry. Various levels of active nuclear factor-kappa B (NF-kappaB) was detected in all malignant glioma cell lines using immunoblotting. The expression of active NF-kappaB and syndecan-1 increased in U251 glioma cells after tumor necrosis factor-alpha or interleukin-1beta treatment, which can activate NF-kappaB. The amplification of active NF-kappaB and syndecan-1 by tumor necrosis factor-alpha or interleukin-1beta was suppressed by an inhibitor of NF-kappaB activation (emodin). Emodin also downregulated the expression of syndecan-1 mRNA in U251 cells. These results indicate that malignant glioma cells express all types of syndecans and suggest that NF-kappaB participates in the upregulation of the syndecan-1 expression at the transcriptional level, and increased expression of syndecan-1 could associate with extracellular matrices including thrombospondin-1.
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PMID:Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. 1613 27

Cell adhesion and spreading is a crucial step in the metastatic cascade of cancer cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Emodin is the major active component of the rhizome of Rheum palmatum L., with known anticancer activities. Here, we first found that emodin significantly inhibited cell adhesion of various human cancer cells. This inhibition was achieved through suppressing the recruitment of focal adhesion kinase (FAK) to integrin beta(1) as well as the phosphorylation of FAK followed by the decreased formation of focal adhesion complex (FAC). In understanding the underlying mechanisms, we found that emodin inhibited the lipid raft clustering and subsequent colocalization of integrin beta(1) and FAC proteins within lipid rafts. Lipid profile analysis revealed significant decrease of cholesterol and sphingolipids in raft fraction after emodin treatment. Cholesterol replenishment abolished the adverse effect of emodin on the translocation of integrin beta(1) and FAC proteins into the lipid raft fraction and cell adhesion. Therefore, data from this study provide novel evidence that emodin inhibits cell adhesion and spreading through disruption of the membrane lipid raft-associated integrin signaling pathway.
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PMID:Emodin inhibits tumor cell adhesion through disruption of the membrane lipid Raft-associated integrin signaling pathway. 1674 Jul 20

Anthraquinones represent a large family of compounds having diverse biological properties. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a naturally occurring anthraquinone present in the roots and barks of numerous plants, molds, and lichens, and an active ingredient of various Chinese herbs. Earlier studies have documented mutagenic/genotoxic effects of emodin, mainly in bacterial system. Emodin, first assigned to be a specific inhibitor of the protein tyrosine kinase p65lck, has now a number of cellular targets interacting with it. Its inhibitory effect on mammalian cell cycle modulation in specific oncogene overexpressed cells formed the basis of using this compound as an anticancer agent. Identification of apoptosis as a mechanism of elimination of cells treated with cytotoxic agents initiated new studies deciphering the mechanism of apoptosis induced by emodin. At present, its role in combination chemotherapy with standard drugs to reduce toxicity and to enhance efficacy is pursued vigorously. Its additional inhibitory effects on angiogenic and metastasis regulatory processes make emodin a sensible candidate as a specific blocker of tumor-associated events. Additionally, because of its quinone structure, emodin may interfere with electron transport process and in altering cellular redox status, which may account for its cytotoxic properties in different systems. However, there is no documentation available which reviews the biological activities of emodin, in particular, its growth inhibitory effects. This review is an attempt to analyze the biological properties of emodin, a molecule offering a broad therapeutic window, which in future may become a member of anticancer armamentarium.
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PMID:Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent. 1701 78

The experimental researches of applying emodin for prevention and treatment of liver diseases in recent years were reviewed. Emodin can inhibit the growth of liver tumor cells in vitro and in vivo, inducing cell apoptosis is one of its mechanisms. Emodin also has the effects of liver protection, anti-liver fibrosis, and so on, the mechanisms for those effects still need more studies.
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PMID:[Experimental advance of applying emodin for prevention and treatment of liver diseases]. 1841 81

Emodin, a natural anthraquinone compound isolated from the rhizome of rhubarb, is reported to suppress the growth of tumor in many clinical situations. In this study, we focused on the effect of emodin in human breast cancer BCap-37 cells and further understand the underlying molecular mechanism in treating breast cancer. Using MTT assay and flow cytometry, we demonstrated the critical role of emodin in the suppression of the proliferation of BCap-37 cells based on a concentration-and time-dependent manner. The increase of apoptotic rate was also observed after incubation of BCap-37 cells on emodin at 20 microM and 50 microM for 48 h. The cells exhibited typical apoptotic features including cellular morphological change, chromatin condensation and membrane blebbing. The results of the study further showed that Bcl-2 level decreased, while Bax and cytosolic cytochrome c levels in sample cells increased after the emodin treatment by using Western blot. The decline in the Bcl-2/Bax ratio and the increase of cytosolic cytochrome c concentration were consistent with the increase of the apoptotic ratio. The results strongly suggest that the disruption of the mitochondrial signaling pathway was involved in emodin-induced apoptosis in BCap-37 cells.
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PMID:Emodin-induced apoptosis in human breast cancer BCap-37 cells through the mitochondrial signaling pathway. 1856 56


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