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

Abstract

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.

• Authors: T Kurosu, K Tsuji, A Kida, T Koyama, M Yamamoto, O Miura
• Journal: Oncogene (Oncogene) Vol. 26 Issue 21 Pg. 2975-87 (May 10 2007) ISSN: 0950-9232 [Print] England
• PMID: 17130834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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