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Histamine and spontaneously released mast cell granules affect the cell growth of human hepatocellular carcinoma cells
Full text linkThe role of mast cells in tumor growth is still controversial. In this study we analyzed the effects of both histamine and pre-formed mediators spontaneously released by mast cells on the growth of two human hepatocellular carcinoma cell lines, HA22T/VGH and HuH-6, with different characteristics of differentiation, biological behavior and genetic defects. We showed that total mast cell releasate, exocytosed granules (granule remnants) and histamine reduced cell viability and proliferation in HuH-6 cells. In contrast, in HA22T/VGH cells granule remnants and histamine induced a weak but significant increase in cell growth. We showed that both cell lines expressed histamine receptors H1 and H2 and that the selective H1 antagonist terfenadine reverted the histamine-induced inhibition of HuH-6 cell growth, whereas the selective H2 antagonist ranitidine inhibited the histamine-induced cell growth of HA22T/VGH cells. We demonstrated that histamine down-regulated the expression of β-catenin, COX-2 and survivin in HuH-6 cells and that this was associated with caspase-3 activation and PARP cleavage. On the contrary, in HA22T/VGH cells expression of survivin and β-catenin increased after treatment with granule remnants and histamine. Overall, our results suggest that mediators stored in mast cell granules and histamine may affect the growth of liver cancer cells. However, mast cells and histamine may play different roles depending on the tumor cell features. Finally, these data suggest that histamine and histamine receptor agonists/antagonists might be considered as "new therapeutic" drugs to inhibit liver tumor growth
Poly (ADP-ribose) polymerase inhibition synergizes with the NF-κB inhibitor DHMEQ to kill hepatocellular carcinoma cells
No full textPoly (ADP-ribose) polymerase (PARP) enzymes play a key role in the cellular machinery responsible for DNA repair. Dehydroxymethylepoxyquinomicin (DHMEQ), a new inhibitor of NF-κB, induces oxidative stress and DNA damage. The effects of DHMEQ in combination with Olaparib (PARP inhibitor) were studied on hepatocellular carcinoma (HCC) cells. The DHMEQ-Olaparib combination synergistically inhibited cell viability, cell proliferation and colony formation of Hep3B, but had additive effects on Huh7 cells. The synergistic effects of the combination correlated with increased apoptosis, caspase 3/7 activity and PARP cleavage. There was an induction of an endoplasmic reticulum (ER) stress response with significant up-regulation of CHOP and TRB3 genes and splicing of XBP1 mRNA in Hep3B cells but not in Huh7 cells. Silencing of the TRB3 mRNA in Hep3B cells reversed the reduction in viability caused by DHMEQ-Olaparib treatment, while depletion of unspliced XBP1 mRNA in DHMEQ-Olaparib-treated Huh7 cells reduced viability. ROS production was increased after DHMEQ-Olaparib treatment of Hep3B, which caused DNA damage by an accumulation of γH2AX, increased AKT phosphorylation and reduced cell viability. The combination reduced Rad51 nuclear foci in Hep3B cells (not Huh7 cells), and silencing of Rad51 enhanced sensitivity of Huh7 cells to the DHMEQ-Olaparib combination. Knockdown of AKT in Hep3B cells restored the number of Rad51 nuclear foci after DHMEQ-Olaparib treatment. In summary, the DHMEQ-Olaparib combination induced ROS production, which killed HCC cells via DNA damage that could not be repaired by Rad51. Summary: PARPs and NF-κB are frequently deregulated in HCC. The DHMEQ-Olaparib combination exerted synergistic anti-tumour effects on HCC cells through ROS production via DNA damage that could not be repaired by Rad51. This suggested that the DHMEQ-Olaparib combination could be used to treat tumours that were resistant to Olaparib treatment. © 2014 Elsevier B.V
SOLID LIPID NANOPARTICLES CONTAINING NIMESULIDE: PREPARATION, CHARACTERIZATION AND CYTOTOXICITY STUDIES
No full textThe prospect of improved cancer therapy using Solid Lipid Nanoparticles (SLNs) as drug delivery system is promising. Several obstacles frequently encountered with anticancer compounds, such as poor drug solubility, are overcome by delivering them using SLN. Moreover, the intravenous administration of drugs into SLNs can potentially enhance drug blood circulation time and improve drug performance by inducing accumulation into tumours by enhanced permeability and retention (EPR) effect. This paper deals with the development of SLN containing nimesulide, a non-steroidal anti-inflammatory drug with antitumour effect and low solubility in water. Here, SLNs carrying nimesulide were prepared and characterized, and the antiproliferative effect of drug-loaded SLN versus free drug on HT-29 and SW-480 cell lines was here evaluated. All the obtained systems possess colloidal size, ranging from 85 to 132 nm and negative zeta potential values. Moreover these systems show good loading capacity and drug release profile, and an in vitro antitumour activity comparable to free dru
Antitumor effects of the selective cycloxygenase-1 inhibitor SC-560 is potentiated by inhibition of MEK/ERK pathway in human hepatocellular cells.
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Influence of MEK/ERK signaling on apoptosis induced by selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatocellular carcinoma cells
No full textInhibition of the MEK/ERK pathway enhances apoptosis induced by selective COX-1 and COX-2 inhibitors in human hepatocellular carcinoma cells
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