lb-100 and Carcinoma--Hepatocellular

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The multikinase inhibitor sorafenib is the only clinically proved systematic treatment for HCC. However, few patients respond to sorafenib. Hypoxic microenvironments contribute to sorafenib resistance. LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor was previously found to be a chemosensitizer in HCC. Here, we tested whether LB-100 could sensitize HCC to the effects of sorafenib. Intriguingly, LB-100 enhanced the effects of sorafenib in HCC cells only during hypoxic environments. LB-100 dramatically increased intracellular p-Smad3 level, which was responsible for the effect of LB-100 as a sensitizer. LB-100 downregulated Bcl-2 expression and enhanced sorafenib-induced apoptosis in HCC cells. We further proved that PP2A mediated LB-100-induced p-Smad3 overexpression. In addition, p38 mitogen-activated protein kinase pathway was activated in hypoxic conditions, and enhanced p-Smad3-dependent Bcl-2 inhibition and consequent apoptosis. In conclusion, LB-100 sensitized HCC cells to sorafenib in hypoxic environments. This effect was mediated by inactivation of PP2A, resulting in enhanced level of p-Smad3. Increased p-Smad3 downregulated Bcl-2, causing increased apoptosis of HCC cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Hepatocellular; Cell Hypoxia; Cell Line, Tumor; Drug Synergism; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Smad3 Protein; Sorafenib; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is one of the most common and therapeutically challenging malignancies worldwide. For patients ineligible for "curative resection" or liver transplantation, chemotherapy is an important minimally effective option. Strategies for chemosensitization are urgently needed. Here, we report that LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor, enhances the cytotoxicity of chemotherapy for HCC in vitro and in vivo. We found that LB-100 significantly enhanced inhibition of HCC by doxorubicin and cisplatin in vitro and in vivo in a PP2A-dependent way, while having little inhibitory activity when used alone. LB-100 promoted vascular endothelial growth factor secretion and vasculogenic mimicry, associated with increased microvessel density and blood perfusion of tumor cell xenografts. LB-100 also enhanced paracellular endothelial permeability to Evans Blue dye and doxorubicin in vivo and in vitro, presumably by altering vascular endothelial-cadherin contact between cells. Changes in permeability and perfusion were accompanied by increased accumulation of doxorubicin in HCC xenografts but not in normal liver tissue. In conclusion, LB-100 enhances chemotherapy by interfering with DNA damage-induced defense mechanisms and by increasing angiogenesis and drug penetration into tumor cells. The induction of angiogenesis and vascular permeability of tumor xenografts by inhibition of PP2A may be a novel approach for enhancing the cytotoxic treatment of HCC and potentially other cancers.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Membrane Permeability; Cisplatin; Doxorubicin; Drug Synergism; Human Umbilical Vein Endothelial Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms, Experimental; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Piperazines; Protein Phosphatase 2; Tumor Burden; Xenograft Model Antitumor Assays