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The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in

Ryosuke Inoue1, Nori-aki Matsuki, Gao Jing

  • 1Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka, Japan.

British Journal of Pharmacology
|August 16, 2005
PubMed

Insights

Alendronate, a bisphosphonate, inhibits the PI3K-Akt-NFkappaB cell survival pathway by blocking PI3K activation. This finding reveals new therapeutic targets for alendronate in cancer treatment.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Bisphosphonates inhibit tumor cell growth and bone resorption via apoptosis.
  • The precise mechanisms by which bisphosphonates induce apoptosis are not fully understood.
  • The phosphoinositide 3-kinase (PI3K)-Akt-NFkappaB pathway is a critical regulator of cell survival.

Purpose of the Study:

  • To investigate the effect of alendronate on the PI3K-Akt-NFkappaB cell survival pathway.
  • To elucidate the specific molecular targets of alendronate within this pathway.

Main Methods:

  • Utilized the osteosarcoma cell line MG-63, stimulated with tumor necrosis factor-alpha or insulin.
  • Assessed pathway activation by measuring phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) production, PI3K activity, Akt phosphorylation, and IkappaB kinase (IKK) activity.
  • Examined the impact of alendronate pretreatment on these molecular events, including experiments with proteasome inhibitors and geranylgeraniol.

Main Results:

  • Alendronate partially inhibited IkappaB phosphorylation and degradation, and IKK activity.
  • Alendronate significantly inhibited Akt phosphorylation and PtdIns(3,4,5)P(3) production, indicating PI3K pathway inhibition.
  • The inhibitory effects were not reversed by geranylgeraniol, suggesting a mechanism independent of isoprenoid lipid substrate replenishment.

Conclusions:

  • Alendronate effectively inhibits the PI3K-Akt-NFkappaB cell survival pathway.
  • The primary inhibitory action of alendronate occurs at the level of PI3K activation.
  • These findings identify novel molecular targets for alendronate, potentially expanding its therapeutic applications.

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