Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-invasive therapies for the treatment of hepatocellular carcinoma (HCC) would be of great benefit to public health. To this end, we have developed a platelet-derived growth factor-C (PDGF-C) transgenic (Tg) mouse model, which mimics many aspects of human liver carcinogenesis. Specifically, overexpression of PDGF-C results in liver fibrosis, which is preceded by activation and proliferation of hepatic stellate cells, and is followed by the development of dysplastic lesions and angiogenesis, and progression to HCCs by 8 months of age. Here, we show that PDGF-C overexpression induces the proliferation of endothelial-like cells that are present in tumors and adjacent non-neoplastic parenchyma. The protein tyrosine kinase inhibitor, imatinib (Gleevec), decreases the proliferation of non-parenchymal cells (NPC) in vitro and in vivo, with concomitant inhibition of Akt. In vivo treatment with imatinib also blocks the expression of CD34 in PDGF-C Tg mice. Decreased NPC proliferation and CD34 expression correlated with lower levels of active ERK1/2 and total levels of PDGF receptor alpha (PDGFRalpha). In summary, the small molecule inhibitor imatinib attenuates stromal cell proliferation in PDGF-C-induced HCC, which coincides with decreased expression of both CD34 and PDGFRalpha, and activated Akt. Our findings suggest that imatinib may be efficacious in the treatment of hepatocarcinogenesis, particularly when neovascularization is present.
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PMID:Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis. 1799 42

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease caused by the oncoprotein BCR-ABL, which exhibits a constitutive tyrosine kinase activity. Imatinib mesylate (IM), an inhibitor of the tyrosine kinase activity of BCR-ABL, has been used as a first-line therapy for CML. However, IM is less effective in the accelerated phase and blastic phases of CML and certain patients develop IM resistance due to the mutation and amplification of the BCR-ABL gene. Fangchinoline, an important chemical constituent from the dried roots of Stephaniae tetrandrae S. Moore, exhibits significant antitumor activity in various types of cancers, including breast, prostate and hepatocellular carcinoma. However, the effects and the underlying mechanisms of fangchinoline in CML remain unclear. In the present study, we identified that fangchinoline inhibits cell proliferation in a dose- and time-dependent manner in K562 cells derived from the blast crisis of CML. Additional experiments revealed that fangchinoline induces cell cycle arrest at the G0/G1 phase and has no effect on apoptosis, which is mediated through the upregulation of cyclin-dependent kinase (CDK)-N1A and MCL-1 mRNA levels, as well as the downregulation of cyclin D2 (CCND2) mRNA levels. These findings suggest the potential of fangchinoline as an effective antitumor agent in CML.
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PMID:Fangchinoline induces G0/G1 arrest by modulating the expression of CDKN1A and CCND2 in K562 human chronic myelogenous leukemia cells. 2359 78

The elevated level of copper is one of the hallmark features of cancer cells in most of the types of cancer. In the present study, this feature has been targeted to investigate if coadministration of exogenous copper (Cu+) and its chelating agent like disulfiram (DSF+) influence the antineoplastic activity of the anticancer drug, Gleevec (GLV+), in hepatocellular carcinoma (HCC)-induced rats via immunomodulation. After the treatment, the level of proinflammatory interleukins (IL-1, 2, 6, and 7), anti-inflammatory interleukin (IL-10) concomitant with transcription factors (NF-kB and TNF-a), and the apoptotic marker (cleaved PARP) was estimated. The cancer-induced group without treatment (CN+) demonstrated abnormally elevated level of all proinflammatory cytokines and transcription factors concomitant with a compromised level of cleaved PARP as compared to the control normal (CN-). The detailed histological analysis also supported the results exhibiting extensive inflammation and tissue fibrosis confirming the second stage of HCC. Cu+, DSF+, and GLV+ displayed mild improvement in most of the parameters, but the combination group GLV + Cu+ demonstrated remarkable recovery in histology and most of the parameters tended towards the CN- followed by GLV + DSF+. Therefore, the management of copper level is critical in realizing the antineoplastic activity of GLV up to its full potential in cancer treatment. These findings will help in improving chemoimmunotherapy and personalized cancer treatment.
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PMID:Copper Mediates Anti-Inflammatory and Antifibrotic Activity of Gleevec in Hepatocellular Carcinoma-Induced Male Rats. 3094 31