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Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells

Sowmyalakshmi Srinivasan1, Srinivas Koduru, Raj Kumar

  • 1Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, KY 40536-0200, USA.

International Journal of Cancer
|April 23, 2009
PubMed

Insights

Diosgenin, a compound from fenugreek, inhibits Akt signaling and downstream targets in both estrogen receptor-positive and negative breast cancer cells. This dietary compound shows potential as a chemotherapeutic agent with no observed toxicity in normal cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Akt signaling pathway is crucial in aggressive, therapy-resistant cancers.
  • Constitutive activation of Akt signaling is common in cancer cells, making it a therapeutic target.
  • Diosgenin is a dietary compound with potential anti-cancer properties.

Purpose of the Study:

  • To investigate the effect of diosgenin on Akt signaling and its downstream targets in estrogen receptor-positive (ER(+)) and estrogen receptor-negative (ER(-)) breast cancer cells.
  • To evaluate diosgenin's impact on cell cycle progression, proliferation, and apoptosis.
  • To assess the in vivo efficacy and safety of diosgenin in breast cancer models.

Main Methods:

  • Western blotting to assess protein expression (pAkt, PI3K, NF-kappaB, Bcl-2, survivin, XIAP, cyclin D1, cdk-2, cdk-4).
  • Kinase activity assays to measure Akt kinase activity.
  • Cell cycle analysis and apoptosis assays.
  • In vitro toxicity studies on normal breast epithelial cells (MCF-10A).
  • In vivo tumor xenograft studies in nude mice (MCF-7 and MDA-231 models).

Main Results:

  • Diosgenin inhibited pAkt expression and Akt kinase activity, affecting downstream targets like NF-kappaB, Bcl-2, survivin, and XIAP.
  • The Raf/MEK/ERK pathway was inhibited by diosgenin in ER(+) BCa cells but not ER(-) BCa cells.
  • Diosgenin induced G1 cell cycle arrest by downregulating cyclin D1, cdk-2, and cdk-4, inhibiting proliferation and inducing apoptosis in both ER(+) and ER(-) BCa cells.
  • No significant toxicity was observed in normal breast epithelial cells.
  • Diosgenin significantly inhibited tumor growth in both MCF-7 and MDA-231 xenografts in vivo.

Conclusions:

  • Diosgenin effectively inhibits Akt signaling and its downstream pathways in various breast cancer subtypes.
  • Diosgenin demonstrates anti-proliferative and pro-apoptotic effects, leading to cell cycle arrest.
  • Diosgenin shows therapeutic potential as a chemotherapeutic agent for breast cancer with a favorable safety profile.

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