Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas.

Abstract

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.

• Authors: Xue-Li Bai, Qi Zhang, Long-Yun Ye, Qi-Da Hu, Qi-Han Fu, Xiao Zhi, Wei Su, Ri-Ga Su, Tao Ma, Wei Chen, Shang-Zhi Xie, Cong-Lin Chen, Ting-Bo Liang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 8 Pg. 2062-72 (Aug 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24867249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• LB100
• Piperazines
• Doxorubicin
• Protein Phosphatase 2
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage)
• Capillary Permeability (drug effects)
• Carcinoma, Hepatocellular (blood supply, drug therapy, pathology)
• Cell Line, Tumor
• Cell Membrane Permeability
• Cisplatin (administration & dosage)
• Doxorubicin (administration & dosage)
• Drug Synergism
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms, Experimental (blood supply, drug therapy, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (pathology)
• Piperazines (administration & dosage)
• Protein Phosphatase 2 (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays