scholarly journals The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

Oncogene ◽  
2007 ◽  
Vol 27 (22) ◽  
pp. 3102-3110 ◽  
Author(s):  
T Odgerel ◽  
J Kikuchi ◽  
T Wada ◽  
R Shimizu ◽  
K Futaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Leukemic Cells ◽  
Flt3 Inhibitor ◽  
Differential Cell ◽  
Flt3 Mutations

No Evidence for Constitutively Activated FLT3 in Juvenile Myelo-Monocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4915-4915
Author(s):  
Andrica C.H. de Vries ◽  
Ronald W. Stam ◽  
Pauline Schneider ◽  
Charlotte M. Niemeyer ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Leukemic Cells ◽  
Tyrosine Kinase Domain ◽  
Mrna Levels ◽  
Monocytic Leukemia ◽  
Real Time Quantitative Pcr ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations

Abstract Activating FLT3 mutations have been identified as prognostic factors in multiple myeloid malignancies. Recent studies have demonstrated that ligand-independent activation of FLT3 can also result from overexpression of wild-type FLT3. In addition, ligand-dependent activation has been observed in leukemic cells co-expressing FLT3 ligand (FLT3L), resulting in autocrine FLT3 signaling which is independent of FLT3 mutations. In Juvenile Myelo-Monocytic Leukemia (JMML), FLT3 internal tandem duplications (FLT3/ITDs) mutations affecting the tyrosine kinase domain (TKD) are rare. However, no data are yet available on the frequency of expression levels of FLT3 and FLT3L in JMML. If activated FLT3 occurs in JMML, one could imagine that these patients might benefit from treatment with small molecule FLT3 inhibitors, especially as to date the curative treatment of JMML is limited to allogeneous bone marrow transplantation. In 36 JMML patients FLT3 and FLT3L mRNA levels were assessed using real-time quantitative PCR (Taqman). Furthermore these samples were screened for the presence of activating FLT3/ITDs and FLT3/TKD mutations. MTT assays were performed to assess the response of JMML cells to the known FLT3 inhibitor PKC412 (Novartis). FLT3 appeared to be expressed only at basal levels and FLT3L expression was very low. In none of the 36 JMML samples FLT3/ITDs or TDK mutations were found, consistent with the observation that PKC412 was not cytotoxic in JMML samples (n=12), in contrast to leukemic cells of children with ALL which carried an activated FLT3. These data suggest that constitutively activated FLT3 does not occur in JMML. Therefore targeting FLT3 by tyrosine kinase inhibitors like PKC412 is unlikely to be effective in JMML.

Inhibition of Proliferation and Induction of Apoptosis by Thymoquinone via Modulation of TGF Family, p53, p21 and Bcl-2α in Leukemic Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 210-215 ◽  
Author(s):  
Mona Diab-Assaf ◽  
Josiane Semaan ◽  
Marwan El-Sabban ◽  
Soad K. Al Jaouni ◽  
Rania Azar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Apoptosis Induction ◽  
Inhibition Of Proliferation ◽  
Human T Cell

Introduction: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. Objective: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and Methods: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL.

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

2021 ◽  
Vol 64 (19) ◽  
pp. 14664-14701
Author(s):  
Zhijie Wang ◽  
Jiongheng Cai ◽  
Jiwei Ren ◽  
Yun Chen ◽  
Yingli Wu ◽  
...  
Keyword(s):  
Flt3 Inhibitor ◽  
Flt3 Mutations

Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

2017 ◽  
Vol 9 (402) ◽  
pp. eaam8060 ◽  
Author(s):  
Samuel J. Taylor ◽  
Johanna M. Duyvestyn ◽  
Samantha A. Dagger ◽  
Emma J. Dishington ◽  
Catherine A. Rinaldi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Wild Type ◽  
Short Term ◽  
Treatment Regimens ◽  
Multipotent Progenitors ◽  
Flt3 Inhibitor ◽  
Short Term Exposure

We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

scholarly journals Antiproliferative and Apoptosis-Inducing Activities of Benchalokawichian Remedy Against Doxorubicin-Sensitive and -Resistant Erythromyelogenous Leukemic Cells

2021 ◽  
Vol 20 (3) ◽  
Author(s):  
Wipob Suttana ◽  
Chatubhong Singharachai ◽  
Rawiwan Charoensup ◽  
Narawadee Rujanapun ◽  
Chutima Suya
Keyword(s):  
Cell Cycle ◽  
Multidrug Resistance ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Drug Resistant ◽  
Normal Cells ◽  
Root Extracts ◽  
Cycle Arrest

Chemotherapy can cause multidrug resistance in cancer cells and is cytotoxic to normal cells. Discovering natural bioactive compounds that are not cytotoxic to normal cells but inhibit proliferation and induce apoptosis in drug- sensitive and drug-resistant cancer cells could overcome these drawbacks of chemotherapy. This study investigated the antiproliferative effects of crude extracts of Benchalokawichian (BLW) remedy and its herbal components against drug-sensitive and drug-resistant cancer cells, cytotoxicity of the extracts toward normal cells, and their ability to induce apoptosis and cell cycle arrest in drug-sensitive and drug-resistant cancer cells. The extracts exhibited antiproliferative activity against doxorubicin-sensitive and doxorubicin-resistant erythromyelogenous leukemic cells (K562 and K562/adr). Tiliacora triandra root, BLW, and Harrisonia perforata root extracts displayed an IC50 of 77.00 ± 1.30, 79.33 ± 1.33, and 87.67 ± 0.67 µg/mL, respectively, against K562 cells. In contrast, Clerodendrum petasites, T. triandra, and H. perforata root extracts displayed the lowest IC50 against K562/adr cells (68.89 ± 0.75, 78.33 ± 0.69, and 86.78 ± 1.92 µg/mL, respectively). The resistance factor of the extracts was lower than that of doxorubicin, indicating that the extracts could overcome the multidrug resistance of cancer cells. Importantly, the extracts were negligibly cytotoxic to peripheral mononuclear cells, indicating minimal adverse effects in normal cells. In addition, these extracts induced apoptosis of K562 and K562/adr cells and caused cell cycle arrest at the G0/G1 phase in K562 cells. Keywords: Antiproliferative, Apoptosis, Benchalokawichian, Cell cycle, Multidrug resistance

scholarly journals Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3511
Author(s):  
Joseph D. Khoury ◽  
Mehrnoosh Tashakori ◽  
Hong Yang ◽  
Sanam Loghavi ◽  
Ying Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Signaling ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Cyclin B1 ◽  
Leukemic Cells ◽  
Phase Array ◽  
Flt3 Mutations ◽  
The Impact ◽  
Acute Myeloid

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.

scholarly journals The Effect of L-Asparaginase on the Nucleic Acid Metabolism and Cell Cycle of Human Leukemia Cells

Blood ◽  
1972 ◽  
Vol 39 (4) ◽  
pp. 575-580 ◽  
Author(s):  
E. Fred Saunders
Keyword(s):  
Cell Cycle ◽  
Nucleic Acid ◽  
Dna Synthesis ◽  
Rna Synthesis ◽  
Lymphoblastic Leukemia ◽  
Buffy Coat ◽  
Leukemic Cells ◽  
Nucleic Acid Metabolism ◽  
Rapid Decline ◽  
Human Leukemia

Abstract The effect of L-asparaginase on the cell cycle and nucleic acid synthesis of leukemic cells was studied in five children with acute lymphoblastic leukemia. Following an intravenous infusion of the drug, serial marrow samples were obtained for buffy coat volume, mitotic index, and autoradiographic assessment of DNA and RNA synthesis using tritiated thymidine and tritiated uridine, respectively. A rapid decline in buffy coat volume indicated a lytic effect on lymphoblasts. There was a greater kill of proliferative (blasts in the cell cycle) than nonproliferative (G0) leukemic cells. Mitotic indices changed little until 24 hr; in contrast, thymidine labeling indices decreased markedly to less than 50% of control by 6 hr. The changes in labeling indices prior to changes in mitotic indices indicated that L-asparaginase blocked the entrance of cells into the DNA synthesis period of the cell cycle. Cells already in DNA synthesis appeared to continue into mitosis. Uridine labeling indices decreased progressively in all patients. Uridine uptake was inhibited equally in both proliferative and nonproliferative blasts. Therefore, inhibition of RNA synthesis by L-asparaginase was independent of the proliferative activity of the marrow.

Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+exchanger

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1427-1434 ◽  
Author(s):  
Ivan N. Rich ◽  
Diana Worthington-White ◽  
Oliver A. Garden ◽  
Philip Musk
Keyword(s):  
Cell Cycle ◽  
Intracellular Ph ◽  
Annexin V ◽  
Leukemic Cell ◽  
Differential Sensitivity ◽  
Leukemic Cells ◽  
Hematopoietic Tissue ◽  
Leukemic Cell Lines ◽  
Targeted Inhibition

The Na+/H+ exchanger isoform 1 (NHE1) is primarily responsible for the regulation of intracellular pH (pHi). It is a ubiquitous, amiloride-sensitive, growth factor–activatable exchanger whose role has been implicated in cell-cycle regulation, apoptosis, and neoplasia. Here we demonstrate that leukemic cell lines and peripheral blood from primary patient leukemic samples exhibit a constitutively and statistically higher pHi than normal hematopoietic tissue. We then show that a direct correlation exists between pHi and cell-cycle status of normal hematopoietic and leukemic cells. Advantage was taken of this relationship by treating leukemic cells with the Na+/H+ exchanger inhibitor, 5-(N, N-hexamethylene)-amiloride (HMA), which decreases the pHiand induces apoptosis. By incubating patient leukemic cells in vitro with pharmacologic doses of HMA for up to 5 hours, we show, using flow cytometry and fluorescent ratio imaging microscopy, that when the pHi decreases, apoptosis—measured by annexin-V and TUNEL methodologies—rapidly increases so that more than 90% of the leukemic cells are killed. The differential sensitivity exhibited between normal and leukemic cells allows consideration of NHE1 inhibitors as potential antileukemic agents.

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