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

Martinelli, S; Kostylina, G; Niggli, V; Baumann, C; Fey, M F; Wendel, H-G; Lowe, S W; Yousefi, S; Simon, H-U (2006). Targeting survivin via PI3K but not c-akt/PKB by anticancer drugs in immature neutrophils. Oncogene, 25(52), pp. 6915-23. Basingstoke, UK: Nature Publishing Group 10.1038/sj.onc.1209692

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Niggli, Verena; Baumann, Christa Katharina; Fey, Martin; Yousefi, Shida and Simon, Hans-Uwe

ISSN:

0950-9232

ISBN:

16715127

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:45

Last Modified:

04 May 2014 23:13

Publisher DOI:

10.1038/sj.onc.1209692

PubMed ID:

16715127

Web of Science ID:

000241732300002

URI:

https://boris.unibe.ch/id/eprint/18756 (FactScience: 994)

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