title: Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1α-VEGF mediated angiogenesis.
abstract: Pancreatic cancer is a malignant disease without efficient treatment. Improved treatments are urgently needed to enhance or replace chemotherapy. Here we used a small molecular compound LB-100 to assess the effect of pharmacological inhibition of protein phosphatase 2A (PP2A) in combination with doxorubicin on the proliferation of pancreatic cancer in cell lines and a xenograft model. LB-100 moderately reduced PP2A activity and the growth of the cell lines but did not show chemosensitization in vitro. In vivo, however, LB-100 synergistically enhanced the activity of doxorubicin. This effect was associated with increased microvessel density, blood perfusion, and doxorubicin concentrations within the xenografts. Mechanically, LB-100 induced expression of hypoxia-induced factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). In an umbilical vein endothelial cell monolayer model for measuring changes in vascular permeability, increased VEGF secretion following exposure to LB-100 and doxorubicin was accompanied by increased amounts of doxorubicin penetrating the endothelial barrier. In conclusion, PP2A inhibition by LB-100 enhanced the cytotoxicity of doxorubicin in vivo but not in vitro potentially via HIF-1α-VEGF mediated angiogenesis. Combining inhibition of PP2A with chemotherapeutic regimens may enhance their effectiveness against pancreatic cancer.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qida
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Sun
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: liangtingbo@zju.edu.cn.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Liang
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D054648:Protein Phosphatase 2
keywords: Angiogenesis; Chemotherapy sensitization; Drug delivery; Vascular permeability; Xenograft model