Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro. Academic Article uri icon

Overview

abstract

  • Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have 'anti-cancer' activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the expression of key VEGF-effector proteins, including Akt, ERK, Bcl-2 and survivin, and a chemical inhibitor screen discovered relevance of these proteins to cell proliferation. A miRNA microarray revealed that fenofibrate differentially regulated cellular miRNAs with known roles in cancer and angiogenesis. The data raise the possibility that fenofibrate could be useful in angiosarcoma therapy, especially considering its well-established clinical safety and tolerability profile.

publication date

  • April 19, 2019

Research

keywords

  • Cell Division
  • Fenofibrate
  • G2 Phase
  • Hemangiosarcoma
  • Hypolipidemic Agents
  • Neoplasm Proteins
  • PPAR alpha
  • Signal Transduction
  • Vascular Endothelial Growth Factor A

Identity

PubMed Central ID

  • PMC6474884

Scopus Document Identifier

  • 85064562343

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2014.03.006

PubMed ID

  • 31004117

Additional Document Info

volume

  • 9

issue

  • 1