title: 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.affiliation: Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kurosu
authors.forename: K
authors.initials: K
authors.lastname: Tsuji
authors.forename: A
authors.initials: A
authors.lastname: Kida
authors.forename: T
authors.initials: T
authors.lastname: Koyama
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: O
authors.initials: O
authors.lastname: Miura
mesh_terms: D000098:Acetophenones / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000737:chemistry* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D001549:Benzamides; D001578:Benzopyrans; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014475:Uncoupling Agents; D000068877:Imatinib Mesylate; C085746:rottlerin; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D051745:Protein Kinase C-delta