Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and is also highly resistant to conventional chemotherapy treatments. In this study, we report that Longikaurin A (LK-A), an ent-kaurane diterpenoid isolated from the plant Isodon ternifolius, induced cell cycle arrest and apoptosis in human HCC cell lines. LK-A also suppressed tumor growth in SMMC-7721 xenograft models, without inducing any notable major organ-related toxicity. LK-A treatment led to reduced expression of the proto-oncogene S phase kinase-associated protein 2 (Skp2) in SMMC-7721 cells. Lower Skp2 levels correlated with increased expression of p21 and p-cdc2 (Try15), and a corresponding decrease in protein levels of Cyclin B1 and cdc2. Overexpression of Skp2 significantly inhibited LK-A-induced cell cycle arrest in SMMC-7721 cells, suggesting that LK-A may target Skp2 to arrest cells at the G2/M phase. LK-A also induced reactive oxygen species (ROS) production and apoptosis in SMMC-7721 cells. LK-A induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase and P38 MAP kinase. Treatment with, the JNK inhibitor SP600125 prevented LK-A-induced apoptosis in SMMC-7721 cells. Moreover, the antioxidant N-acetylcysteine prevented phosphorylation of both JNK and c-Jun. Taken together, these data indicate that LK-A induces cell cycle arrest and apoptosis in cancer cells by dampening Skp2 expression, and thereby activating the ROS/JNK/c-Jun signaling pathways. LK-A is therefore a potential lead compound for development of antitumor drugs targeting HCC.
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PMID:Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells. 2465 40

Hellebrigenin, one of bufadienolides belonging to cardioactive steroids, was found in skin secretions of toads and plants of Helleborus and Kalanchoe genera. In searching for natural constituents with anti-hepatoma activities, we found that hellebrigenin, isolated from traditional Chinese medicine Venenum Bufonis, potently reduced the viability and colony formation of human hepatocellular carcinoma cells HepG2, and went on to explore the underlying molecular mechanisms. Our results demonstrated that hellebrigenin triggered DNA damage through DNA double-stranded breaks and subsequently induced cell cycle G2/M arrest associated with up-regulation of p-ATM (Ser(1981)), p-Chk2 (Tyr(68)), p-CDK1 (Tyr(15)) and Cyclin B1, and down-regulation of p-CDC25C (Ser(216)). It was also found that hellebrigenin induced mitochondrial apoptosis, characterized by Bax translocation to mitochondria, disruption of mitochondrial membrane potential, release of cytochrome c into cytosol and sequential activation of caspases and PARP. In addition, Akt expression and phosphorylation were inhibited by hellebrigenin, whereas Akt silencing with siRNA significantly blocked cell cycle arrest but enhanced apoptosis induced by hellebrigenin. Activation of Akt by human insulin-like growth factor I (hIGF-I) could obviously attenuate hellebrigenin-induced cell death. In summary, our study is the first to report the efficacy of hellebrigenin against HepG2 and elucidated its molecular mechanisms including DNA damage, mitochondria collapse, cell cycle arrest and apoptosis, which will contribute to the development of hellebrigenin into a chemotherapeutic agent in the treatment of liver cancer.
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PMID:Hellebrigenin induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells through inhibition of Akt. 2495 31

Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of HCC. It was shown that c-MET overexpression predicts its efficacy. Therefore, a phase-3 trial of tivantinib has been initiated to recruit "c-MET-high" patients only. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target. By assessing the mechanisms underlying the anticancer properties of tivantinib we showed that this agent causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1 and Bcl-xl, and by increasing Cyclin B1 expression regardless of c-MET status. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since HGF enhanced the expression of Mcl-1 and Bcl-xl. In summary, we show that the activity of tivantinib is independent of c-MET and describe Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that the predictive effect of c-MET expression in part reflects the c-MET-driven overexpression of Mcl-1 and Bcl-xl in c-MET-high patients and that these molecules are considered as possible response predictors.
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PMID:Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1. 2625 50

Despite having the second highest mortality associated with cancer, currently Sorafenib is the only FDA-approved chemotherapeutic agent available for liver cancer patients which can only improve survival for few months. In this study, various pyrazolic chalcone analogous compounds were synthesized and evaluated as potential chemotherapeutic agents for the treatment of hepatocellular carcinoma (HCC). Modifying the central pyrazole ring at the C(3)-position with different heteroaryl rings and substituting the C(4)-position of pyrazole with differently substituted chalcone moiety produced fouthy two variant compounds. For all these compounds, cytotoxicity was evaluated using sulforhodamine B assay and real time cell growth tracking, respectively. Based on 50% inhibitory concentration (IC50) values, compounds 39, 42, 49, and 52 were shown to exhibit potent cytotoxic activity against all the cancer cell lines tested, and had better cytotoxic activities than the well-known chemotherapeutic drug 5-FU. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Flow cytometric analysis of HCC cells treated with compounds 39, 42, 49, and 52 demonstrated that these compounds caused cell cycle arrest at G2/M phase followed by the apoptotic cell death and impaired cell growth as shown by real-time cell growth surveillance. Consistent with these results, western blotting of HCC cells treated with the compounds resulted in molecular changes for cell cycle proteins, where p21 levels were increased independent of p53 and the levels of the key initiators of mitosis Cyclin B1 and CDK1 were shown to decrease upon treatment. In conclusion, chalcone derivatives 42 and 52 show potent bioactivities by modulating the expression of cell-cycle related proteins and resulting in cell-cycle arrest in the HCC cell lines tested here, indicating that the compounds can be considered as preclinical candidates.
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PMID:Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics. 2821 46

Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy. Therefore, we consider the targeting TPX2 could provide novel therapeutic strategies for cancer. In this study, increased TPX2 protein expression was present in 16 (42%) of 38 primary HCCs and was associated with advanced stage, distant metastatic HCCs and poor prognosis. Knockdown of TPX2 inhibited cancer cell growth and downregulation of cyclin A, cyclin E and CDK2 proteins. However, over-expressed EGFP-TPX2 protein enhanced the in vitro tumor spheroid formation and rescued the TPX2 depleted cell growth. Targeting TPX2 caused a rising impaired chromosomal instability resulting in multinuclearity, cell cycle progression arrest, apotosis, senescence and an increased polyploidy in cells. An image-cytometry analysis revealed cell cycle progression arrest after TPX2 inhibition. A correlation was observed between the downregulation of the protein levels of genes related to chromosomal segregation and spindle assembly checkpoint (securin, seprase, Aurora A, Aurora B, Cyclin B1, Cyclin B2, MPS1, BUB1, BUB3, MAD1 and MAD2) and increased cell ploidy, indicating mitotic progression failure and the loss of the balance of genomic instability. In vitro tumor spheroid assay and in vivo xenografts mouse model showed a therapeutic opportunity. Our findings indicate that targeting TPX2 lead to suppress tumorigenicity in liver cancer cells, suggesting that TPX2 is a potential target for anticancer therapy in HCC.
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PMID:Targeting TPX2 Suppresses the Tumorigenesis of Hepatocellular Carcinoma Cells Resulting in Arrested Mitotic Phase Progression and Increased Genomic Instability. 2863 52

RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 suppressed cell proliferation in culture and resulted in the growth arrest of tumor xenografts, whereas downregulating RBM43 played an opposite role. We have also demonstrated that overexpression or knockdown of RBM43 affects the cell-cycle progression of liver cancer cells. Mechanistically, RBM43 directly associated with the 3'UTR of Cyclin B1 mRNA and regulated its expression. Moreover, loss of Rbm43 in mice promoted liver carcinogenesis and HCC development after diethylnitrosamine (DEN)-carbon tetrachloride (CCl4) treatment. Taken together, our data indicate that RBM43 is a tumor suppressor that controls the cell cycle through modulation of Cyclin B1 expression, providing evidence that RBM43 is particularly important in HCC.
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PMID:RNA-binding motif protein 43 (RBM43) suppresses hepatocellular carcinoma progression through modulation of cyclin B1 expression. 3263 20

Tumor necrosis factor-related apoptotic induction ligand can induce cell apoptosis in various tumor cells. However, many cancer cells are resistant to tumor necrosis factor-related apoptotic induction ligand. Therefore, overcoming the tumor necrosis factor-related apoptotic induction ligand resistance makes it possible for tumor necrosis factor-related apoptotic induction ligand-based anti-cancer therapies. In this study, we took mesenchymal epithelial transition factor as the research target to study its role in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma. Mesenchymal epithelial transition factor gene has been proved to be an effective predictor of recurrence after hepatocellular carcinoma resection. The expression of mesenchymal epithelial transition factor and cyclin B1 were measured in tumor necrosis factor-related apoptotic induction ligand-resistant and non-resistant hepatocellular carcinoma tissues. Cyclin B1-knockdown and cyclin B1-overexpression hepatocellular carcinoma cells were treated with tumor necrosis factor-related apoptotic induction ligand; mesenchymal epithelial transition factor knockout, mesenchymal epithelial transition factor re-introduction and cyclin B1 restored in hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand were established. And MTT, bromodeoxyuridine, flow cytometry and western blotting were performed to evaluate the effect of mesenchymal epithelial transition factor and cyclin B1 on hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand. In addition, subcutaneous tumor transplantation in nude mice was conducted to access the effect of mesenchymal epithelial transition factor and cyclin B1 on tumor formation in vivo. In conclusion, cyclin B1 enhanced the cell growth and inhibited apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells. And mesenchymal epithelial transition factor promoted the cell growth and apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells by regulating cyclin B1. Therefore, mesenchymal epithelial transition factor regulates the cyclin B1 to regulate tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells. Our results suggest a novel molecular mechanism for regulating tumor necrosis factor-related apoptotic induction ligand resistance, which might be helpful to select drug targets in the treatment of liver cancer.
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PMID:Mesenchymal epithelial transition factor regulates tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells through down-regulation of cyclin B1. 3288 4