1. ¹Department of Pharmacology, University of Bern, Bern, Switzerland
2. ²Department of Pathology, University of Bern, Bern, Switzerland
3. ³Institute of Medical Oncology, Inselspital, University of Bern, Bern, Switzerland
4. ⁴Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA

Correspondence: Dr H-U Simon, Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. E-mail: hus@pki.unibe.ch

Received 12 October 2005; Revised 15 February 2006; Accepted 11 April 2006; Published online 22 May 2006.

Abstract

Myelosuppression is the most common unwanted side effect associated with the administration of anticancer drugs, and infections remain a common cause of death in chemotherapy-treated patients. Several mechanisms of the cytotoxicity of these drugs have been proposed and may synergistically operate in a given cell. Survivin expression has been associated with cancer, but recent reports suggest that this molecule is also expressed in several immature and mature hematopoietic cells. Here, we provide evidence that treatment of immature neutrophils with anticancer drugs reduced endogenous survivin levels causing apoptosis. The anticancer drugs did not directly target survivin, instead they blocked the activity of phosphatidylinositol-3-OH kinase, which regulated survivin expression and apoptosis in these cells. Strikingly, and in contrast to other cells, this pathway did not involve the serine/threonine kinase c-akt/PKB. Moreover, in combination with anticancer drug therapy, rapamycin did not induce increased myelosuppression in an experimental lymphoma mouse model. These data suggest that drugs that block either c-akt/PKB or signaling molecules located distal to c-akt/PKB may preferentially induce apoptosis of cancer cells as they exhibit no cytotoxicity for immature neutrophils.