2. Academic Validation
  3. Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1α-VEGF mediated angiogenesis

Inhibition of protein phosphatase 2A sensitizes pancreatic cancer to chemotherapy by increasing drug perfusion via HIF-1α-VEGF mediated angiogenesis

  • Cancer Lett. 2014 Dec 28;355(2):281-7. doi: 10.1016/j.canlet.2014.09.048.
Xueli Bai 1,  Xiao Zhi 2,  Qi Zhang 1,  Feng Liang 3,  Wei Chen 2,  Chao Liang 2,  Qida Hu 2,  Xu Sun 2,  Zhengping Zhuang 4,  Tingbo Liang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 5 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.
PMID: 25304380 DOI: 10.1016/j.canlet.2014.09.048
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.

Keywords

Angiogenesis; Chemotherapy sensitization; Drug delivery; Vascular permeability; Xenograft model.

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