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)

Hepatoblastoma is a primary liver cancer that affects children, due to the sensitivity of this tumor to insulin-like growth factor 1 (IGF-1). In this paper we show that azathioprine (AZA) is capable of inhibiting IGF1-mediated signaling cascade in HepG2 cells. The efficiency of AZA on inhibition of proliferation differs in the evaluated cell lines as follows: HepG2 (an experimental model of hepatoblastoma)>Hep3B (derived from a hepatocellular carcinoma)>HuH6 (derived from a hepatoblastoma)>>HuH7 (derived from a hepatocellular carcinoma)=Chang Liver cells (a non-malignant cellular model). The effect of AZA in HepG2 cells has been proven to derive from activation of Ras/ERK/TSC2, leading to activation of mTOR/p70S6K in a sustained manner. p70S6K phosphorylates IRS-1 in serine 307 which leads to the uncoupling between IRS-1 and p85 (the regulatory subunit of PI3K) and therefore causing the lack of response of HepG2 to IGF-1. As a consequence, proliferation induced by IGF-1 is inhibited by AZA and autophagy increases leading to senescence of HepG2 cells. Our results suggest that AZA induces the autophagic process in HepG2 activating senescence, and driving to deceleration of cell cycle but not to apoptosis. However, when simultaneous to AZA treatment the autophagy was inhibited by bafilomycin A1 and the degradation of regulatory proteins of cell cycle (e.g. Rb, E2F, and cyclin D1) provoked apoptosis. In conclusion, AZA induces resistance in hepatoblastoma cells to IGF-1, which leads to autophagy activation, and causes apoptosis when it is combined with bafilomycin A1. We are presenting here a novel mechanism of action of azathioprine, which could be useful in treatment of IGF-1 dependent tumors, especially in its combination with other drugs.
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PMID:Azathioprine desensitizes liver cancer cells to insulin-like growth factor 1 and causes apoptosis when it is combined with bafilomycin A1. 2395 94

Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte-specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells.
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PMID:B lymphocytes repress hepatic tumorigenesis but not development in Hras12V transgenic mice. 2858 Jun 61

Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and even liver cancer. As the global prevalence of NAFLD rises, it is increasingly important that we understand its pathogenesis and develop effective therapies for this chronic disease. Forkhead box O (FOXO) transcription factors are key downstream regulators in the insulin/insulin-like growth factor 1 (IGF1) signaling pathway, and have been implicated in a range of cellular functions including the regulation of glucose, triglyceride, and cholesterol homeostasis. The role of FOXOs in the modulation of immune response and inflammation is complex, with reports of both pro- and anti-inflammatory effects. FOXOs are reported to protect against hepatic fibrosis by inhibiting proliferation and transdifferentiation of hepatic stellate cells. Mice that are deficient in hepatic FOXOs are more susceptible to non-alcoholic steatohepatitis than wild-type controls. In summary, FOXOs play a critical role in maintaining metabolic and cellular homeostasis in the liver, and dysregulation of FOXOs may be involved in NAFLD development.
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PMID:FOXO transcription factors in non-alcoholic fatty liver disease. 3003 12

Previous evidence revealed significant elevated liver cancer mortality in the areas where water was contaminated with hexavalent chromium [Cr(vi)], which highlighted that we should pay more attention to Cr(vi)-induced cytotoxicity in hepatocytes. We found that Clusterin (CLU) was up-regulated in Cr(vi)-exposed L-02 hepatocytes, but the role CLU played in Cr(vi)-induced cytotoxicity has never been explored. In the present study, we demonstrate Cr(vi) targeted mitochondrial respiratory chain complex I (MRCC I) activity and induced reactive oxygen species (ROS) accumulation, which caused mitochondrial damage that was characterized by the increase of permeability transition pore (PTP) open rate, the collapse of mitochondrial membrane potential (MMP), and the release of apoptosis-inducing factor (AIF) and Cytochrome C (Cyt C) from mitochondria to cytoplasm, which then induced cell viability loss and increased aspartate transaminase (AST)/alanine transaminase (ALT) leakage. We reveal that Cr(vi) may regulate CLU expression through the ROS-ataxia telangiectasia mutant (ATM)-insulin-like growth factor 1 (IGF-1) axis, and CLU expression was positively correlated to MRCC I activity. We further confirmed that CLU may regulate MRCC I activity via modulating its subunit nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) Fe-S protein 3 (NDUFS3) expression. By the establishment of CLU over-expression cells, we found that over-expression of CLU alleviated Cr(vi)-induced MRCC I inhibition and further rescued cell viability loss and reduced AST and ALT leakage. Thus, we reached the conclusion that the CLU-induced increase of MRCC I activity protected against Cr(vi)-induced cytotoxicity. The present research will provide new experimental evidence for thoroughly clarifying the cytotoxicity and the carcinogenic mechanism of Cr(vi).
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PMID:Clusterin increases mitochondrial respiratory chain complex I activity and protects against hexavalent chromium-induced cytotoxicity in L-02 hepatocytes. 3071 57

Diabetes mellitus (DM) and cancer are global problems carrying huge human, social, and economic impact. Type 2 diabetes (T2DM) is associated with an increased risk for a number of cancers, including breast, pancreatic, and liver cancer. Moreover, adverse drug reactions are higher in paitents with cancer with T2DM compared to cancer patients without T2DM. Cellular mechanisms of hyperglycemia and chemotherapy efficacy may be different depending upon the particular cancer type and the condition of the patient. This review evaluates the effect of DM on the pharmacokinetic, pharmacodynamic, and adverse drug reactions of commonly used anticancer drugs such as cisplatin, methotrexate, paclitaxel, doxorubicin, and adriamycin in both clinical and animal models. A literature search was conducted in scientific databases including Web of Science, PubMed, Scopus, and Google Scholar including the relevant keywords. The results of the effectiveness of anticancer therapies in patients with DM are, however, inconsistent because DM can negatively impact multiple diverse entities including nerves and vascular structures, insulin-like growth factor 1, the function of the innate immune system, drug pharmacokinetics, the expression levels of hepatic CYP450 , Mdr 1b and enzymes that then lead to drug toxicity. However, in a few circumstances, DM led to attenuation of the toxicity of anticancer drugs secondary to attenuation of the energy-dependent renal uptake process. Overall, the impact of DM on patients with cancer is variable because of the diverse types of cancers and the spectrum of anticancer drugs. With respect to the evidence for cancer involvement in DM pathophysiology and the response to anticancer treatment in patients with DM, many questions still remain and further clinical trials are needed.
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PMID:The effect of diabetes mellitus on pharmacokinetics, pharmacodynamics and adverse drug reactions of anticancer drugs. 3101 66