Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells

Torquato, Heron Fernandes Vieira; Ribeiro-Filho, Antonio C.; Buri, Marcus V.; Júnior, Roberto T. Araujo; Pimenta, Renata; Oliveira, José Salvador Rodrigues de; Filho, Valdir Cechinel; Macho, Antonio; Paredes‐Gamero, Edgar Julian; Martins, Domingos Tabajara de Oliveira

doi:10.1016/j.bbagen.2017.01.033

Cited by 21 publications

(19 citation statements)

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“…By another alkaloid, the treatment of canthin-6-one has shown elevation of caspase-3, -8, -9 cleavage, reactive oxygen species (ROS), apoptosis signal-regulating kinase 1 (ASK1), p16, p27, p38, p53, c-Jun N-terminal kinases (JNKs), Ki-67 negative population, checkpoint kinase 2 (Chk2), H2A histone family member X (H2A.X), INK4A and Kip1, while mitochondrial membrane potential (MMP) and p- retinoblastoma protein (RB) were shown to be suppressed in Kasumi-1 cells. This result suggests that canthin-6-one effectively promotes various extrinsic and intrinsic apoptotic pathways in Kasumi-1 AML cells [23]. Curine, a natural alkaloid isolated from Chondrodendron platyphyllum , disrupts MMP.…”

Section: Natural Compounds and Acute Myeloid Leukemiamentioning

confidence: 99%

Natural Products and Acute Myeloid Leukemia: A Review Highlighting Mechanisms of Action

et al. 2019

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Recent findings have shown great potential of alternative interventions such as immunotherapy and natural products for acute myeloid leukemia (AML). This study aims to review the anti-AML effect of various natural compounds. Natural compounds were classified into five groups: alkaloids, carotenoids, nitrogen-containing compounds, organosulfur compounds or phenolics based on each compound’s chemical properties. Fifty-eight studies were collected and reviewed in this article. Phenolics are the most abundant group to have an apoptotic effect over AML cells, while other groups have also shown significant apoptotic effects. Some compounds induced apoptosis by regulating unique mechanism like human telomerase reverse transcriptase (hTERT) or laminin receptor (67LR), while others modified caspases, poly (adp-ribose) polymerase (PARP) and p53. Further study is required to identify side-effects of potent compounds and the synergistic effects of combination of two or more natural compounds or existing conventional anti-AML drugs to treat this dreadful disease.

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Section: Natural Compounds and Acute Myeloid Leukemiamentioning

confidence: 99%

Natural Products and Acute Myeloid Leukemia: A Review Highlighting Mechanisms of Action

et al. 2019

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“…Moreover, it also induced cell differentiation as defined by morphological alteration and the presence of β -tubulin III and TH, the mature neuronal markers. Cell apoptotic detection was not found in our study, although it was strongly related to cell differentiation and growth arrest/inhibition of cell proliferation [42]. However, the whole process on how metformin promotes cell differentiation still needs to be further clarified.…”

Section: Discussionmentioning

confidence: 71%

Metformin Promotes Neuronal Differentiation via Crosstalk between Cdk5 and Sox6 in Neuroblastoma Cells

Binlateh

Tanasawet

Rattanaporn

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Metformin has recently emerged as a key player in promotion of neuroblastoma differentiation and neurite outgrowth. However, molecular mechanisms of how metformin promotes cellular differentiation have not yet been fully elucidated. In this study, we investigated how metformin promotes cell differentiation, via an inhibition of cell proliferation, by culturing SH-SY5Y neuroblastoma cells with or without metformin. Pretreatment with reactive oxygen species (ROS) scavenger, NAC, revealed that ROS plays a crucial role in induction of cell differentiation. Cell differentiation was observed under various morphological criteria: extension of neuritic processes and neuronal differentiation markers. Treatment with metformin significantly increased neurite length, number of cells with neurite, and expression of neuronal differentiation markers, β-tubulin III and tyrosine hydroxylase (TH) compared with untreated control. Further investigation found that metformin significantly decreased Cdk5 but increased Sox6 during cell differentiation. Analysis of the mechanism underlying these changes using Cdk5 inhibitor, roscovitine, indicated that expressions of Cdk5 and Sox6 corresponded to metformin treatment. These results suggested that metformin produces neuronal differentiation via Cdk5 and Sox6. In addition, phosphorylated Erk1/2 was decreased while phosphorylated Akt was increased in metformin treatment. Taken together, these findings suggest that metformin promotes neuronal differentiation via ROS activation through Cdk5/Sox6 crosstalk, relating to Erk1/2 and Akt signaling.

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“…Indeed, though DFX treatment induced NAC-sensitive upregulation of the differentiation markers of the myeloid lineage, this did not translate in an increase of the CFU-GM. A possible explanation might stem on the more mature differentiation stage of Kasumi-1 and HL60 (as compared to K562 (M2 versus M1)), which further boosts towards lineage commitment and maturation by DFX hampering their ability to form colonies as already described [33]. Unlike Kasumi-1 cells, ROS-dependent activity of DFX to form colonies was not confirmed in HL60 maybe because of their peculiar susceptibility to NAC exposure [34].…”

Section: Discussionmentioning

confidence: 99%

Deferasirox drives ROS-mediated differentiation and induces interferon-stimulated gene expression in human healthy haematopoietic stem/progenitor cells and in leukemia cells

et al. 2019

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Background Administration of the iron chelator deferasirox (DFX) in transfusion-dependent patients occasionally results in haematopoiesis recovery by a mechanism remaining elusive. This study aimed to investigate at a molecular level a general mechanism underlying DFX beneficial effects on haematopoiesis, both in healthy and pathological conditions. Methods Human healthy haematopoietic stem/progenitor cells (HS/PCs) and three leukemia cell lines were treated with DFX. N -Acetyl cysteine (NAC) and fludarabine were added as antioxidant and STAT1 inhibitor, respectively. In vitro colony-forming assays were assessed both in healthy and in leukemia cells. Intracellular and mitochondrial reactive oxygen species (ROS) as well as mitochondrial content were assessed by cytofluorimetric and confocal microscopy analysis; mtDNA was assessed by qRT-PCR. Differentiation markers were monitored by cytofluorimetric analysis. Gene expression analysis (GEA) was performed on healthy HS/PCs, and differently expressed genes were validated in healthy and leukemia cells by qRT-PCR. STAT1 expression and phosphorylation were assessed by Western blotting. Data were compared by an unpaired Student t test or one-way ANOVA. Results DFX, at clinically relevant concentrations, increased the clonogenic capacity of healthy human CD34 + HS/PCs to form erythroid colonies. Extension of this analysis to human-derived leukemia cell lines Kasumi-1 , K562 and HL60 confirmed DFX capacity to upregulate the expression of specific markers of haematopoietic commitment. Notably, the abovementioned DFX-induced effects are all prevented by the antioxidant NAC and accompanied with overproduction of mitochondria-generated reactive oxygen species (ROS) and increase of mitochondrial content and mtDNA copy number. GEA unveiled upregulation of genes linked to interferon (IFN) signalling and tracked back to hyper-phosphorylation of STAT1 . Treatment of leukemic cell lines with NAC prevented the DFX-mediated phosphorylation of STAT1 as well as the expression of the IFN-stimulated genes. However, STAT1 inhibition by fludarabine was not sufficient to affect differentiation processes in leukemic cell lines. Conclusions These findings suggest a significant involvement of redox signalling as a major regulator of multiple DFX-orchestrated events promoting differentiation in healthy and tumour cells. The understanding of molecular mechanisms underlying the haematological response by DFX would enable to predict patient’s ability to respond to the drug, to extend treatment to other patients or to anticipate the treatment, regardless of the iron overload. Electronic supplementary material The online version of this article (10.1186/s13287-019-1293-y) contains sup...

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Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells

Abstract: Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity.

Cited by 21 publications

References 50 publications

Natural Products and Acute Myeloid Leukemia: A Review Highlighting Mechanisms of Action

Natural Products and Acute Myeloid Leukemia: A Review Highlighting Mechanisms of Action

Metformin Promotes Neuronal Differentiation via Crosstalk between Cdk5 and Sox6 in Neuroblastoma Cells

Deferasirox drives ROS-mediated differentiation and induces interferon-stimulated gene expression in human healthy haematopoietic stem/progenitor cells and in leukemia cells

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