O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia

Yen, Shih-Chung; Wu, Yiwen; Huang, Chen-Chiao; Chao, Min Wu; Tu, Huang‐Ju; Chen, Liang-Chieh; Lin, Tony Eight; Sung, Tzu-Ying; Tseng, Hui-Ju; Chu, Jung-Chun; Huang, Wei‐Jan; Yang, Chung-May; HuangFu, Wei-Chun; Pan, Shiow‐Lin; Hsu, Kai‐Cheng

doi:10.1016/j.phymed.2022.154061

Cited by 5 publications

(9 citation statements)

References 69 publications

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“…O-methylated flavonol, a precursor of fisetin, inhibited the activity of FLT3-ITD and FLT3-D835Y kinases. 244 Moreover, FLT3-ITD MOLM-13 and MV4-11 cells, when treated with this flavonol, arrested cell cycle at the G0/G1 phase and activated apoptotic proteins such as PARP, caspase 3, and BAX. 244 …”

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 92%

“… 244 Moreover, FLT3-ITD MOLM-13 and MV4-11 cells, when treated with this flavonol, arrested cell cycle at the G0/G1 phase and activated apoptotic proteins such as PARP, caspase 3, and BAX. 244 …”

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 92%

“…247 OncoTargets and Therapy 2022:15 https://doi.org/10.2147/OTT.S384293 DovePress 1469 Dovepress O-methylated flavonol, a precursor of fisetin, inhibited the activity of FLT3-ITD and FLT3-D835Y kinases. 244 Moreover, FLT3-ITD MOLM-13 and MV4-11 cells, when treated with this flavonol, arrested cell cycle at the G0/G1 phase and activated apoptotic proteins such as PARP, caspase 3, and BAX. 244 Isoliquiritigenin extracted from licorice root also demonstrated anti-cancer activity by targeting FLT3.…”

Section: Flavonoids In Flt3 Amlmentioning

confidence: 92%

“… 11 These compounds work as anti-oxidant, anti-bacterial, anti-viral, anti-inflammatory, and anti-cancer agents. 244 Only flavones and flavonols are suggested to be anti-cancer agents among flavonoids due to their ability to induce mitochondria-mediated apoptosis and suppress multiple signaling pathways including MAPK, PI3K, and NF-κB. 11 Hispidulin, luteolin, acacetin, and eupatin, subgroups of flavones and flavonols, are shown to have inhibitory properties towards FLT3.…”

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 99%

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Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

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Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 92%

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 92%

Section: Flavonoids In Flt3 Amlmentioning

confidence: 92%

Section: Targeted Flt3 Aml Therapeutics Beyond Flt3 Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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“…Kaempferol was shown to decrease cell viability in tested acute promyelocytic cell lines with an associated decrease in Akt, BCL2, ABCB1, and ABCC1 genes expression, while the expression of CASP3 and BAX/BCL-2 ratio were significantly increased ( 50 ). Recently, an O-methylated flavonol was shown to target multiple kinases that play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 ( 51 ). Thus, it can be developed as a novel therapeutic for drug-resistant acute myeloid leukemias.…”

Section: Flavonoidsmentioning

confidence: 99%

Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies

Izuegbuna

2022

Front. Nutr.

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Polyphenols are one of the largest plant-derived natural product and they play an important role in plants’ defense as well as in human health and disease. A number of them are pleiotropic molecules and have been shown to regulate signaling pathways, immune response and cell growth and proliferation which all play a role in cancer development. Hematological malignancies on the other hand, are cancers of the blood. While current therapies are efficacious, they are usually expensive and with unwanted side effects. Thus, the search for newer less toxic agents. Polyphenols have been reported to possess antineoplastic properties which include cell cycle arrest, and apoptosis via multiple mechanisms. They also have immunomodulatory activities where they enhance T cell activation and suppress regulatory T cells. They carry out these actions through such pathways as PI3K/Akt/mTOR and the kynurenine. They can also reverse cancer resistance to chemotherapy agents. In this review, i look at some of the molecular mechanism of action of polyphenols and their potential roles as therapeutic agents in hematological malignancies. Here i discuss their anti-proliferative and anti-neoplastic activities especially their abilities modulate signaling pathways as well as immune response in hematological malignancies. I also looked at clinical studies done mainly in the last 10–15 years on various polyphenol combination and how they enhance synergism. I recommend that further preclinical and clinical studies be carried out to ensure safety and efficacy before polyphenol therapies be officially moved to the clinics.

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MNK Proteins as Therapeutic Targets in Leukemia

Mazewski¹,

Platanias²

2023

OTT

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In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have been identified as important activators of oncogenic-related signaling and may be mediators of resistance. Recent studies in leukemia models, especially acute myeloid leukemia (AML), have focused on targeting MNKs together with other inhibitors or treating chemotherapy-resistant cells with MNK inhibitors. The preclinical demonstrations of the efficacy of MNK inhibitors in these combination formats would suggest a promising potential for use in clinical trials. Optimizing MNK inhibitors and testing in leukemia models is actively being pursued and may have important implications for the future. These studies are furthering the understanding of the mechanisms of MNKs in cancer which could translate to clinical studies.

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O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia

Cited by 5 publications

References 69 publications

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies

MNK Proteins as Therapeutic Targets in Leukemia

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