Rottlerin synergistically enhances imatinib-induced apoptosis of BCR/ABL-expressing cells through its mitochondrial uncoupling effect independent of protein kinase C-delta

Oncogene. 2007 May 10;26(21):2975-87. doi: 10.1038/sj.onc.1210117. Epub 2006 Nov 27.


Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL), relapse with emerging imatinib-resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we demonstrate that rottlerin, a putative protein kinase C-delta (PKCdelta)-specific inhibitor, acts synergistically with imatinib to induce apoptosis of BCR/ABL-expressing K562 and Ton.B210 cells. However, rottlerin inhibited neither PKCdelta nor BCR/ABL in these cells. On the other hand, rottlerin, previously characterized also as a mitochondrial uncoupler, transiently but significantly reduced mitochondrial membrane potential and gradually induced mitochondrial membrane permeabilization. Moreover, two other mitochondrial uncouplers, FCCP and DNP, very similarly induced apoptosis of BCR/ABL-expressing cells in a synergistic manner with imatinib. Imatinib synergistically enhanced mitochondrial membrane permeabilization induced by mitochondrial uncouplers, which led to release of cytochrome c into the cytoplasm and activation of caspases-3 and -9. Rottlerin also enhanced the cytotoxic effect of imatinib in leukemic cells from patients with CML blast crisis and Ph-positive ALL or a cell line expressing the imatinib-resistant E255K BCR/ABL mutant. The present study indicates that rottlerin synergistically enhances imatinib-induced apoptosis through its mitochondrial uncoupling effect independent of PKCdelta and may contribute to the development of new treatment strategy to overcome the imatinib resistance and to cure the BCR/ABL expressing leukemias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / chemistry*
  • Acetophenones / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis* / drug effects
  • Benzamides
  • Benzopyrans / chemistry*
  • Benzopyrans / pharmacology
  • Drug Synergism
  • Fusion Proteins, bcr-abl
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Erythroblastic, Acute / drug therapy
  • Leukemia, Erythroblastic, Acute / enzymology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Piperazines / pharmacology*
  • Protein Kinase C-delta / physiology*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / biosynthesis
  • Protein-Tyrosine Kinases / genetics*
  • Pyrimidines / pharmacology*
  • Uncoupling Agents / chemistry*
  • Uncoupling Agents / pharmacology
  • Up-Regulation / drug effects


  • Acetophenones
  • Antineoplastic Agents
  • Benzamides
  • Benzopyrans
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Uncoupling Agents
  • Imatinib Mesylate
  • rottlerin
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Protein Kinase C-delta