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Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway

Hyun-Jung Byun1, Jeong Heon Lee, Boh-Ram Kim

  • 1Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyevonggi-do 410-769, Republic of Korea.

Microvascular Research
|October 2, 2012
PubMed

Insights

Thioridazine, an anti-psychotic drug, shows novel anti-cancer effects by inhibiting angiogenesis. It effectively suppresses ovarian cancer cell growth and related functions without harming normal cells, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Thioridazine is an antipsychotic with known anti-tumor properties.
  • Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
  • Novel anti-angiogenic agents are needed for cancer therapy.

Purpose of the Study:

  • To investigate thioridazine's potential as an anti-angiogenic agent.
  • To assess its effects on cancer cell proliferation and angiogenesis-related processes.
  • To elucidate the molecular mechanisms underlying its anti-angiogenic activity.

Main Methods:

  • Assessed thioridazine's effect on ovarian cancer cell lines (OVCAR-3, 2774) and normal cell types.
  • Evaluated inhibition of vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cell (HUVEC) migration, proliferation, invasion, and tube formation in vitro.
  • Analyzed the impact of thioridazine on key signaling pathways, including focal adhesion kinase (FAK), Akt, and mammalian target of rapamycin (mTOR), downstream of αvβ3 integrin.

Main Results:

  • Thioridazine significantly inhibited the growth of ovarian cancer cells but not normal cells.
  • It suppressed VEGF-stimulated HUVEC migration, proliferation, invasion, and capillary-like tube formation in a dose- and time-dependent manner.
  • Thioridazine inhibited the phosphorylation of signaling molecules (Akt, PDK-1, mTOR, p70S6K) downstream of αvβ3 integrin and FAK, without affecting ERK phosphorylation.

Conclusions:

  • Thioridazine exhibits novel anti-angiogenic properties by targeting the αvβ3/FAK/mTOR signaling pathway.
  • These findings support thioridazine's potential as a therapeutic agent for suppressing angiogenesis-mediated cancer cell proliferation.
  • The drug selectively targets cancer cells, sparing normal cell types.

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