The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling.
We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, Kcl-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFRalpha, FLT-3, and c-KIT genes, respectively, with IC(50)s of <30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFRalpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy.
Ikezoe
Takayuki
T
Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan. ikezoet@med.kochi-u.ac.jp
Nishioka
Chie
C
Tasaka
Taizo
T
Yang
Yang
Y
Komatsu
Naoki
N
Togitani
Kazuto
K
Koeffler
H Phillip
HP
Taguchi
Hirokuni
H
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007211:Indoles; D010750:Phosphoproteins; D011758:Pyrroles; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D020794:Receptor Protein-Tyrosine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus