Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL

Abstract

Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-d is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL. Blockade of protein kinase C-d (PKC-d) 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-d might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and nonmitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death. Herein we report that the inhibition of PKC-d decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Dw. 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-d is a promising new target in the combat against CLL.

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

“…Previous work, on cells other than CLLs, indicated that 4HPR promotes Mcl-1 downregulation through PKCdelta cleavage and activation. 30,31 However, PKCdelta was already active in our untreated CLLs, in accordance with previous work demonstrating constitutive activation of PKCdelta in CLL cells 40,41 and antiapoptotic, instead of death-promoting, activity in these cells. 41,42 Altogether, different from other cell systems, in CLL cells PKCdelta appeared not to participate in 4HPR apoptosis or Mcl-1 downregulation.…”

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

“…In fact, PKC displays opposing effects in T cell apoptotic mechanisms, and their balance determines the final fate of the cell. When rottlerin is used at Ն10 M, it causes unspecific blockade of several PKCs as well as the inhibition of CD3/CD28 signaling pathway, which culminates in Fas-mediated cell death (10,(57)(58)(59)(60). However, doses Ͻ6.0 M proved to be highly specific for PKC inhibition and kept the viability of PBLs and Jurkat mostly at basal levels.…”

NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells

“…6), and an increase in cell death (Fig. 3k), a phenomenon observed in other cells such as chronic lymphocytic leukemia cells [30], suggesting that the endogenous PKCδ activity may be necessary for cell survival and/or proliferation. Taken together, these data indicate that NSC actions involve differential molecular targets in different cells, and further support the concept that the effects of PKCδ are highly relevant to cellular context, which may be mediated via distinct pathways [31].…”