Decitabine and all-trans retinoic acid synergistically exhibit cytotoxicity against elderly AML patients via miR-34a/MYCN axis

Cao, Yang; Liu, Yue; Shang, Limei; Wei, Wei; Shen, Yangling; Gu, Qisheng; Xie, Xian-Jin; Dong, Weimin; Yang, Lin; Yue, Yanhua; Wang, Fei; Gu, Weiying

doi:10.1016/j.biopha.2020.109878

Cited by 16 publications

(24 citation statements)

References 61 publications

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“…All clinical studies that investigated the effects of atRA in non-APL AML to date used different protocols [15], which may contribute to the inconsistency of their results. Possibly the most promising effects were obtained when atRA was combined with hypomethylating agents [15,79,80]. The relative timing, as well as the duration of the administration of the different drugs are also likely to be important: addition of atRA prior to or together with chemotherapy may optimize the sensitization to cytotoxic drugs, while maximal effects of retinoids on LSC elimination may be achieved when using them as maintenance therapy.…”

Section: Discussionmentioning

confidence: 99%

“…It should be pointed out that all discussed trials differed in numerous parameters, including patient age, the identities of the cytotoxic drugs used in conjunction with atRA, and treatment schedules, thereby precluding direct comparisons. In contrast to the so far mostly disappointing results regarding the combination of atRA with conventional chemotherapy, two recent studies suggested that atRA may be beneficial when combined with hypomethylating agents in elderly patients ineligible for induction chemotherapy [79,80]. It is assumed that hypomethylating treatment primes myeloid differentiation genes for transcription activation by RARs [81].…”

Section: Atra In Non-apl Aml: Clinical Trialsmentioning

confidence: 99%

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All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. All-trans retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML. Attempts to identify genetically or molecularly defined subgroups of patients that may respond to atRA have not yielded consistent results. Since AML is a stem cell-driven disease, understanding the effectiveness of atRA may require an appreciation of its impact on AML stem cells. Recent studies reported that atRA decreased stemness of AML with an FLT3-ITD mutation, yet increased it in AML1-ETO driven or EVI1-overexpressing AML. This review summarizes the role of atRA in normal hematopoiesis and in AML, focusing on its impact on AML stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Atra In Non-apl Aml: Clinical Trialsmentioning

confidence: 99%

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

et al. 2020

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“…A justifiable answer seems to be possible by recruiting different gene set by inviting different RNA-machineries. Nevertheless, The microRNA; miR-150, miR-34a and miR-29b has also shown significant anti-leukemia effect by targeting wnt-signalling, mammalian target of rapamycin (mTOR)-signalling pathways [79] Myc [81] and Sp1/FUT4-fucosylations [83]. In addition to this, the immune-based therapeutics should also consider in AML treatment by utilizing dendritic cells, T-cells and NK cell-targeting CISH-mediated signalling [87,89,95].…”

Section: Discussionmentioning

confidence: 99%

“…miR-34a was shown to be another microRNA playing a crucial role in controlling elderly AML, who were ineligible for conventional chemotherapy. The author [81] have found that, the combination of decitabine (dacogen/DAC; known as 5-aza-2'-deoxycytidine) and all-trans retinoic acid (ATRA; a well-known differentiation inducing agent) effectively control AML and prolong overall survival rate by 49.6% in a clinical trial of 36-elderly leukemia patients. The underlying mechanism demonstrates that the combination of DAC and ATRA inhibited the expression of DNA methyltransferase 1 (DNMT1) resulting in activation of miR-34a by hypo methylation.…”

Section: Mir-34a In Amlmentioning

confidence: 99%

“…The activated miR-34a further inhibits the expression of Myc [43,44] resulting in cell cycle arrest and increased apoptosis in vitro. This result suggests that miR-34a could be a druggable candidate to control AML progression by modulating miR-34a/Myc axis [81,82]. ; demonstrated that miR-29b is also playing an important role in controlling (LSCs) leukemia stem cell progression, a subtype of acute myeloid leukemia, characterized by increased self-renewal capacity and decreased apoptosis, by targeting LSC-fucosylation.…”

Section: Mir-34a In Amlmentioning

confidence: 99%

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Immunotherapeutic Potential of m6A-Modifiers in Controlling Acute Myeloid Leukemia

Kumar¹,

Nagpal²,

Kumar³

et al. 2021

Preprint

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Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have been predominantly focused on DNA methylation, histone modifications and chromatin remodelling. However, recently, RNA modification (m6A-methylation) also termed ‘epitranscriptomics’ has emerged as a new layer of epigenetic regulation due to its diverse role in various biological processes. In this review, we have summarized the therapeutic potential of m6A-modifiers in controlling haematological disorders especially acute myeloid leukemia (AML). It is a type of blood cancer affecting specific subsets of blood-forming hematopoietic stem/progenitor cells (HSPCs) which proliferate rapidly and acquire self-renewable capacities with impaired terminal cell-differentiation and apoptosis leading to abnormal accumulation of white blood cells, and thus an alternative therapeutic approach is required urgently. Here, we have described how RNA m6A-modification machineries EEE (Editor/writer: Mettl3, Mettl14; Eraser/remover: FTO, ALKBH5 and Effector/reader: YTHDF-1/2) could be reformed into potential druggable candidate or as RNA modifying drug (RMD) to treat leukemia. Moreover, we have shed-light on the role of microRNA and suppressor of cytokine signalling (SOCS/CISH) in increasing anti-tumor immunity towards leukemia. We anticipate, our investigation will provide a fundamental knowledge in nurturing the potential of RNA modifiers in discovering novel therapeutics or immunotherapeutic procedures.

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Fast proliferating and slowly migrating non‐small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment

Pelos,

Riester,

Pal

et al. 2023

Intl Journal of Cancer

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Non‐small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes. In our study, we test the efficacy of the DNA‐hypomethylating agent decitabine (DAC) in combination with all‐trans retinoic acid (ATRA), which has been shown to possess little systemic adverse effects. Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG‐I or RARB partially reversed the sensitivity of KRAS‐mutant NCI‐H460 cells. To study resistance, we generated two NCI‐H460 cell populations resistant to ATRA and DAC, which migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence. In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC.

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Decitabine and all-trans retinoic acid synergistically exhibit cytotoxicity against elderly AML patients via miR-34a/MYCN axis

Cited by 16 publications

References 61 publications

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

Immunotherapeutic Potential of m6A-Modifiers in Controlling Acute Myeloid Leukemia

Fast proliferating and slowly migrating non‐small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment

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