Targeting survivin via PI3K but not c-akt/PKB by anticancer drugs in immature neutrophils.
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.
Martinelli
S
S
Department of Pharmacology, University of Bern, Bern, Switzerland.
Kostylina
G
G
Niggli
V
V
Baumann
C
C
Fey
M F
MF
Wendel
H-G
HG
Lowe
S W
SW
Yousefi
S
S
Simon
H-U
HU
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001853:Bone Marrow / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000187:drug effects*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D020123:Sirolimus / Q000009:adverse effects; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D000077022:Survivin
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents; D004317:Doxorubicin; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D000077022:Survivin; C107489:BIRC5 protein, human