Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model

BMC Cancer. 2016 Mar 7:16:191. doi: 10.1186/s12885-016-2225-1.


Background: Group IVA cytosolic phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.

Methods: Mice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or α-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann-Whitney U tests (α = 0.05) were performed on all other data.

Results: Glycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2α inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors.

Conclusions: These results demonstrate that cPLA2α inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2α inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Neoplasms, Basal Cell / drug therapy
  • Neoplasms, Basal Cell / metabolism
  • Neoplasms, Basal Cell / pathology*
  • Neovascularization, Pathologic* / drug therapy
  • Neovascularization, Pathologic* / metabolism
  • Phospholipase A2 Inhibitors / pharmacology*
  • Phospholipases A2, Cytosolic / metabolism
  • Triple Negative Breast Neoplasms / diagnosis
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism
  • Tumor Burden / drug effects
  • X-Ray Microtomography
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Phospholipase A2 Inhibitors
  • Phospholipases A2, Cytosolic
  • Dinoprostone