Kinase Inhibitors and Interferons as Other Myeloid Differentiation Inducers in Leukemia Therapy

Takahashi, Shinichiro

doi:10.1159/000519769

Cited by 8 publications

(6 citation statements)

References 65 publications

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“…We found that TCN (Akt inhibitor), SB202190, PD169316, CAY10571, SB203580 (p38 MAPK inhibitor) and several other inhibitors increased the expression of CD11b ( Fig 1B ), and this was confirmed by FCM analysis ( Fig 2A ). p38 MAPK inhibitors were reported to be involved in myeloid differentiation [ 5 ]; therefore, we focused on TCN because it has not been identified as a myeloid differentiation inducer, and is well tolerated in patients with advanced hematological malignancies [ 12 ]. We assessed the time-course effect of TCN on NB4 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Many kinase inhibitors have been reported to induce differentiation, including cyclin-dependent kinase inhibitors, glycogen synthesis kinase 3 inhibitors, Akt inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitors [ 5 ]. In the current study, we identified novel myeloid differentiation inducers using a Kinase Inhibitor Screening Library and found that triciribine (TCN) was an effective myeloid differentiation inducer.…”

Section: Introductionmentioning

confidence: 99%

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Identification of triciribine as a novel myeloid cell differentiation inducer

Suzuki,

Sato-Nagaoka

et al. 2024

PLoS ONE

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Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and tolerance development of ATRA need to be improved, we searched for another efficient myeloid differentiation inducer. Kinase activation is involved in leukemia biology and differentiation block. To identify novel myeloid differentiation inducers, we used a Kinase Inhibitor Screening Library. Using a nitroblue tetrazolium dye reduction assay and real-time quantitative PCR using NB4 APL cells, we revealed that, PD169316, SB203580, SB202190 (p38 MAPK inhibitor), and triciribine (TCN) (Akt inhibitor) potently increased the expression of CD11b. We focused on TCN because it was reported to be well tolerated by patients with advanced hematological malignancies. Nuclear/cytoplasmic (N/C) ratio was significantly decreased, and myelomonocytic markers (CD11b and CD11c) were potently induced by TCN in both NB4 and acute myeloid leukemia (AML) M2 derived HL-60 cells. Western blot analysis using NB4 cells demonstrated that TCN promoted ERK1/2 phosphorylation, whereas p38 MAPK phosphorylation was not affected, suggesting that activation of the ERK pathway is involved in TCN-induced differentiation. We further examined that whether ATRA may affect phosphorylation of ERK and p38, and found that there was no obvious effect, suggesting that ATRA induced differentiation is different from TCN effect. To reveal the molecular mechanisms involved in TCN-induced differentiation, we performed microarray analysis. Pathway analysis using DAVID software indicated that “hematopoietic cell lineage” and “cytokine-cytokine receptor interaction” pathways were enriched with high significance. Real-time PCR analysis demonstrated that components of these pathways including IL1β, CD3D, IL5RA, ITGA6, CD44, ITGA2B, CD37, CD9, CSF2RA, and IL3RA, were upregulated by TCN-induced differentiation. Collectively, we identified TCN as a novel myeloid cell differentiation inducer, and trials of TCN for APL and non-APL leukemia are worthy of exploration in the future.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of triciribine as a novel myeloid cell differentiation inducer

Suzuki,

Sato-Nagaoka

et al. 2024

PLoS ONE

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“…Induction of blast cell differentiation is emerging as a promising strategy, not only against acute promyelocytic leukemia, but also in the AML field [ 129 ]. A CDK2-targeted proteolysis-targeting chimera (PROTAC) has been developed to selectively degrade CDK2 while sparing the other CDKs [ 124 ].…”

Section: Novel Molecules Targeting Proliferative Mechanisms In Acute ...mentioning

confidence: 99%

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

et al. 2023

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Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kd, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

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“…Accumulated evidences suggests that abnormal activation of signal transduction pathways plays a pivotal role in leukemogenesis, through the blocking of differentiation and abnormal cell proliferation [ 5 ]. Kinase inhibitors can serve as differentiation inducers, and the author recently described the application of kinase inhibitors for differentiation therapy in AML [ 6 ]. Therefore, targeting kinase activity is considered an attractive therapeutic strategy to overcome AML.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the expansion of differentiation therapy for clinical application outside of APL may be attractive for improving clinical outcomes [ 4 ]. The author recently described the application of kinase inhibitors for differentiation therapy in AML [ 6 ]. Clinical trials for kinase modulators as single agents remain scarce and have shown limited effects [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Therapies with Kinase Inhibitors for Acute Myeloid Leukemia Treatment

Takahashi

2023

Hematology Reports

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Targeting kinase activity is considered to be an attractive therapeutic strategy to overcome acute myeloid leukemia (AML) since aberrant activation of the kinase pathway plays a pivotal role in leukemogenesis through abnormal cell proliferation and differentiation block. Although clinical trials for kinase modulators as single agents remain scarce, combination therapies are an area of therapeutic interest. In this review, the author summarizes attractive kinase pathways for therapeutic targets and the combination strategies for these pathways. Specifically, the review focuses on combination therapies targeting the FLT3 pathways, as well as PI3K/AKT/mTOR, CDK and CHK1 pathways. From a literature review, combination therapies with the kinase inhibitors appear more promising than monotherapies with individual agents. Therefore, the development of efficient combination therapies with kinase inhibitors may result in effective therapeutic strategies for AML.

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Kinase Inhibitors and Interferons as Other Myeloid Differentiation Inducers in Leukemia Therapy

Cited by 8 publications

References 65 publications

Identification of triciribine as a novel myeloid cell differentiation inducer

Identification of triciribine as a novel myeloid cell differentiation inducer

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

Combination Therapies with Kinase Inhibitors for Acute Myeloid Leukemia Treatment

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