Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL.
Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-delta is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL. Blockade of protein kinase C-delta (PKC-delta) by the highly specific inhibitor rottlerin induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. By co-culturing bone marrow stromal and CLL cells, we determined that the proapoptotic effect of rottlerin is not abolished in the presence of survival factors, indicating that a targeted therapy against PKC-delta might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and non-mitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death. Herein we report that the inhibition of PKC-delta decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Deltapsi. In addition, we discovered that ZAP-70-expressing cells are significantly more susceptible to rottlerin-induced cell death than ZAP-70 negative cells. We finally observed that rottlerin can augment cell toxicity induced by standard chemotherapeutic drugs. Conclusively, PKC-delta is a promising new target in the combat against CLL.
Ringshausen
I
I
3rd Department of Medicine, Technical University of Munich, Munich, Germany. iringshausen@cc.ucsf.edu
Oelsner
M
M
Weick
K
K
Bogner
C
C
Peschel
C
C
Decker
T
T
D000098:Acetophenones / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; C085746:rottlerin; D051746:ZAP-70 Protein-Tyrosine Kinase; D051745:Protein Kinase C-delta; D020169:Caspases