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The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1

I Ben Sahra1, K Laurent, A Loubat

  • 1INSERM U568, Nice, France.

Oncogene
|January 24, 2008
PubMed

Insights

Metformin, an antidiabetic drug, significantly inhibits prostate cancer cell proliferation and reduces tumor growth in mice. Its anti-cancer effects involve blocking the cell cycle, not inducing apoptosis, with potential mechanisms independent of AMP kinase pathway activation.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Metformin is a common antidiabetic medication known for regulating glucose metabolism.
  • Emerging evidence suggests metformin may possess anti-cancer properties, but its precise mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the effects of metformin on human prostate cancer cell proliferation in vitro and in vivo.
  • To elucidate the molecular mechanisms underlying metformin's potential anti-cancer activity.

Main Methods:

  • Assessing metformin's impact on the viability and proliferation of prostate cancer cell lines (DU145, PC-3, LNCaP) and a normal prostate epithelial cell line (P69).
  • Analyzing cell cycle progression, apoptosis, and protein expression (cyclin D1, pRb, p27kip) in response to metformin treatment.
  • Investigating the role of AMP-activated protein kinase (AMPK) pathway by using siRNA to inhibit its subunits.
  • Evaluating metformin's efficacy in reducing tumor growth in mouse xenograft models (LNCaP).

Main Results:

  • Metformin significantly inhibited the proliferation of prostate cancer cells, with a 50% decrease in viability, while having a modest effect on normal cells.
  • Metformin blocked the cell cycle at the G(0)/G(1) phase, decreasing cyclin D1 and pRb phosphorylation, and increasing p27kip expression, without inducing apoptosis.
  • AMPK pathway activation was observed, but its inhibition did not abolish metformin's antiproliferative effect.
  • In vivo studies showed metformin reduced tumor growth by 50% (oral) and 35% (intraperitoneal) and decreased cyclin D1 levels in tumors.

Conclusions:

  • Metformin exhibits significant antiproliferative effects on human prostate cancer cells in vitro and reduces tumor growth in vivo.
  • The anti-cancer mechanism of metformin in prostate cancer involves cell cycle arrest at G(0)/G(1) and modulation of key cell cycle regulatory proteins, potentially independent of AMPK.
  • These findings support the investigation of metformin as a potential therapeutic or preventative agent for prostate cancer.

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