Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia

DeRemer, David L.; Üstün, Celalettin; Natarajan, Kavita

doi:10.1016/j.clinthera.2008.11.014

Cited by 147 publications

(103 citation statements)

References 62 publications

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“…A drug cocktail including another apoptotic molecule such as ceramide could be a good way to obtain better preclinical models in order to reduce side effects and define effective combinations. Although nilotinib is highly specific for Phþ cells, there is still a possibility of evolving adverse effects [35,36]. This is why providing successful treatment in the clinic without using high-dose nilotinib is an important goal.…”

Section: Discussionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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In this study, we aimed to increase the sensitivity of human K562 and Meg-01 chronic myeloid leukemia (CML) cells to nilotinib by targeting bioactive sphingolipids, in addition to investigating the roles of ceramide metabolizing genes in nilotinib induced apoptosis. Cytotoxic effects of nilotinib, C8:ceramide, glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) inhibitors were determined by XTT cell proliferation assay and synergism between the agents was determined by isobologram analysis. Also, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results demonstrated that expression levels of longevity assurance (LASS) genes in response to nilotinib were correlated with sensitivity to nilotinib. For the first time, The results of this study showed for the first time that nilotinib induces apoptosis through upregulating ceramide synthase genes and downregulating SK-1 in CML cells in addition to inhibition of BCR/ABL. On the other hand, manipulating bioactive sphingolipids toward generation/accumulation of ceramides increased the apoptotic effects of nilotinib in CML cells.

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Section: Discussionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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“…This suggests that blockade of PDGFR by imatinib mesylate may reduce megakaryocytopoiesis leading to thrombocytopenia, highlighting a crucial role for PDGF receptors in megakaryocytopoiesis. Since PDGFR appear to participate in the pathogenesis of many human malignancies, it is not surprising that newer anti-tyrosine kinase inhibitors other than imatinib mesylate, such as sunitinib 41 and nilotinib 42 , which also inhibit PDGFR kinase activity and their downstream signal molecules, could induce thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

Ye¹,

Chan²,

Qiao³

et al. 2010

Haematologica

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BackgroundPlatelet-derived growth factor is involved in the regulation of hematopoiesis. Imatinib mesylate, a platelet-derived growth factor receptor inhibitor, induces thrombocytopenia in a significant proportion of patients with chronic myeloid leukemia. Although our previous studies showed that platelet-derived growth factor enhances megakaryocytopoiesis in vitro, the in vivo effect of platelet-derived growth factor in a model of radiation-induced thrombocytopenia has not been reported. Design and MethodsIn this study, we investigated the effect of platelet-derived growth factor on hematopoietic stem/progenitor cells and platelet production using an irradiated-mouse model. We also explored the potential molecular mechanisms of platelet-derived growth factor on thrombopoiesis in M-07e cells. ResultsPlatelet-derived growth factor, like thrombopoietin, significantly promoted the recovery of platelets and the formation of bone marrow colony-forming unit-megakaryocyte in irradiated mice. Histology confirmed the protective effect of platelet-derived growth factor, as shown by an increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, platelet-derived growth factor had a similar anti-apoptotic effect as thrombopoietin on megakaryocytes. We also demonstrated that platelet-derived growth factor activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. ConclusionsOur findings show that platelet-derived growth factor enhances platelet recovery in mice with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via platelet-derived growth factor receptors with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockage of platelet-derived growth factor receptors may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.Key words: platelet-derived growth factor, thrombopoiesis, imatinib mesylate, thrombocytopenia, apoptosis. PI3-k/Akt pathway. Haematologica 2010;95(10):1745-1753. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Ye JY, Chan GC, Qiao L, Lian Q, Meng FI, Luo Q, Khachigian LM, Ma M, Deng R, Chen JL, Chong BH, and Yang M, Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

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“…12,22 The mechanism of action is similar to that of imatinib, but 32 of the known 33 mutations in the BCR-ABL fusion protein responsible for imatinib resistance remain ineffective to develop resistance against nilotinib. 23 Enhanced specificity and efficacy of nilotinib make it possible to obtain similar amounts of therapeutic effect in lower concentrations, which could only be provided by considerably high concentrations of imatinib. Imatinib treatment might not be tolerated well in aged patients, which brings along the necessity of using a more selective drug.…”

Section: Discussionmentioning

confidence: 99%

Nilotinib significantly induces apoptosis in imatinib resistant K562 cells with wild-type BCR–ABL, as effectively as in parental sensitive counterparts

et al. 2010

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TurkeyChronic myeloid leukemia (CML) is a hematological malignancy characterized by high levels of immature white blood cells. CML is caused by the translocation between chromosomes 9 and 22 (which results in the formation of the Philadelphia chromosome) creating BCR-ABL fusion protein.Imatinib and nilotinib are chemotherapeutic drugs which specifically bind to the BCR-ABL and inhibit cancer cells. Nilotinib is more effective in this respect than imatinib. We have shown that nilotinib induces apoptosis in imatinib-resistant K562 CML cells which have the wild-type BCR-ABL fusion gene almost to the same extent as it does in the parental sensitive cells by the increase in caspase-3 enzyme activity and the decrease in mitochondrial membrane potential. This effect of nilotinib, even in low concentrations, may indicate the efficacy of the usage of nilotinib in imatinib-resistant CML with less risk of undesired cytotoxic effects in the remaining cells of the body.

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Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia

Cited by 147 publications

References 62 publications

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

Nilotinib significantly induces apoptosis in imatinib resistant K562 cells with wild-type BCR–ABL, as effectively as in parental sensitive counterparts

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