Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives

Sobhanifar, Mohammad-Ali; Mashkani, Baratali; Saadatmandzadeh, Mohammad; Sadeghnia, Hamid Reza; Mousavi, Seyed Hadi

doi:10.1016/j.biopha.2018.09.001

Cited by 3 publications

(2 citation statements)

References 42 publications

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“…As was discussed earlier, up-regulation of anti-apoptotic and down-regulation of pro-apoptotic proteins is a known major mechanism of resistance to FLT3 inhibitor therapy that may be circumvented with the addition of venetoclax. One report showed that FLT3-ITD cells have higher level of Bcl-2 compared to FLT3 wildtype cells 80. In addition, venetoclax primary and secondary resistance appears to be driven by FLT3-ITD mutation 81.…”

Section: Limitation and Future Directionmentioning

confidence: 99%

<p>Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection</p>

Abbas¹,

Alfayez²,

Kadia³

et al. 2019

CMAR

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Fms-related-tyrosine kinase 3 (FLT3) mutations occur in approximately a third of acute myeloid leukemia (AML) patients and confer an adverse prognosis. Numerous studies have evaluated FLT3 targeting as single agent and in combination approaches in frontline and relapsed AML. At this time, midostaurin, a multikinase inhibitor, is the only FLT3-inhibitor that is US FDA approved to be used in combination with induction therapy in the frontline FLT3-mutated AML setting based on improved overall survival noted in the RATIFY Phase III trial. The utility of midostaurin in maintenance post stem cell transplantation has shown promising results and further studies are still ongoing. In this review, we discuss the studies that led to the inception of midostaurin as a targeted kinase inhibitor, its evaluation in AML, the early clinical trials and the large Phase III clinical trial that led to its eventual US FDA-approval in FLT3-mutated AML. Our review also discusses data on midostaurin adverse effects, mechanisms of resistance and limitations of its utility. We further discuss emerging second-generation FLT3 inhibitors, with a focus on quizartinib and gilteritinib and future directions to enhance FLT3-inhibitor efficacy and overcome mechanisms of resistance.

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Section: Limitation and Future Directionmentioning

confidence: 99%

<p>Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection</p>

Abbas¹,

Alfayez²,

Kadia³

et al. 2019

CMAR

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“…Hole et al reported that AML cells can escape the oxidative damage by inhibiting p38 MAPK -mediated cycle arrest and/or apoptotic signaling [ 27 ]. Besides, it was found that the expression or activity of pro-apoptotic proteins, e.g., B-cell lymphoma 2 (Bcl-2) antiagonist of cell death (Bad) and Bcl-2-associated X protein (Bax) are inhibited in FLT3-ITD AML cells [ 56 , 57 ], whereas the expression or activity of pro-survival proteins, e.g., B-cell lymphoma extra large (Bcl-xL), Bcl-2 or myeloid cell leukemia-1 (MCL-1) are upregulated, which is conducive to AML cells’ survival [ 35 , 58 – 60 ]. Therefore, inhibiting the antioxidant capacity of leukemia cells, amplifying oxidative stress signaling, and restoring/activating apoptotic pathways may help to eradicate AML cells [ 61 – 65 ].…”

Section: Redox Control Is Crucial To the Survival Of Amlmentioning

confidence: 99%

NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia

Chen,

Zou,

Găman

et al. 2023

Cell Death Discov.

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The internal tandem duplication of the juxtamembrane domain of the FMS-like tyrosine kinase 3 (FLT3-ITD) is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs harbor a FLT3-ITD mutation. Even though FLT3 inhibitors have displayed encouraging effects in FLT3-ITD-mutated AML, the extent of the clinical response to these compounds is cut short due to the rapid development of drug resistance. Evidence has shown that FLT3-ITD triggered activation of oxidative stress signaling may exert a pivotal role in drug resistance. The downstream pathways of FLT3-ITD, including STAT5, PI3K/AKT, and RAS/MAPK, are considered to be major oxidative stress signaling pathways. These downstream pathways can inhibit apoptosis and promote proliferation and survival by regulating apoptosis-related genes and promoting the generation of reactive oxygen species (ROS) through NADPH oxidase (NOX) or other mechanisms. Appropriate levels of ROS may promote proliferation, but high levels of ROS can lead to oxidative damage to the DNA and increase genomic instability. In addition, post-translational modifications of FLT3-ITD and changes in its subcellular localization can affect downstream signaling which may also be one of the mechanisms leading to drug resistance. In this review, we summarized the research progress on NOX mediated oxidative stress signaling and its relationship with drug resistance in FLT3-ITD AML, and discuss the possible new targets in FLT3-ITD signal blocking to reverse drug resistance in FLT3-ITD-mutated AML.

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Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry

Yadav

Shah

2021

Bioorganic Chemistry

141

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Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives

Cited by 3 publications

References 42 publications

<p>Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection</p>

<p>Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection</p>

NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia

Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry

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