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Published on: August 21, 2013

Targeting survivin via PI3K but not c-akt/PKB by anticancer drugs in immature neutrophils

S Martinelli1, G Kostylina, V Niggli

  • 1Department of Pharmacology, University of Bern, Bern, Switzerland.

Oncogene
|May 23, 2006
PubMed

Insights

Anticancer drugs reduce survivin levels in immature neutrophils by blocking phosphatidylinositol-3-OH kinase, leading to apoptosis. This pathway spares neutrophils, suggesting targeted cancer therapy with reduced myelosuppression.

Area of Science:

  • Hematology
  • Cancer Biology
  • Pharmacology

Background:

  • Myelosuppression is a major side effect of anticancer drugs, increasing infection risk.
  • Survivin, a molecule associated with cancer, is also expressed in hematopoietic cells.
  • Understanding drug mechanisms in hematopoietic cells is crucial for safe cancer therapy.

Purpose of the Study:

  • To investigate the effect of anticancer drugs on survivin expression and apoptosis in immature neutrophils.
  • To elucidate the signaling pathway regulating survivin and apoptosis in these cells.
  • To assess the potential for developing targeted therapies with reduced myelosuppression.

Main Methods:

  • Treatment of immature neutrophils with various anticancer drugs.
  • Analysis of survivin levels and apoptosis induction.
  • Investigation of the phosphatidylinositol-3-OH kinase/c-akt/PKB signaling pathway.
  • Evaluation of rapamycin's effect on myelosuppression in a lymphoma mouse model.

Main Results:

  • Anticancer drugs reduced endogenous survivin levels in immature neutrophils, inducing apoptosis.
  • This effect was mediated by blocking phosphatidylinositol-3-OH kinase, not directly targeting survivin.
  • The pathway in neutrophils did not involve c-akt/PKB, unlike in other cell types.
  • Rapamycin, combined with anticancer therapy, did not increase myelosuppression in a mouse model.

Conclusions:

  • Drugs blocking phosphatidylinositol-3-OH kinase or downstream signaling molecules may selectively induce cancer cell apoptosis.
  • This targeted approach could minimize cytotoxicity to immature neutrophils, reducing myelosuppression.
  • The distinct signaling pathway in neutrophils offers a potential therapeutic window for cancer treatment.

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