Epigallocatechin‐3‐gallate enhances differentiation of acute promyelocytic leukemia cells via inhibition of PML‐RARα and HDAC1

Moradzadeh, Maliheh; Roustazadeh, Abazar; Tabarraei, Alijan; Erfanian, Saiedeh; Sahebkar, Amirhossein

doi:10.1002/ptr.5990

Cited by 25 publications

(29 citation statements)

References 42 publications

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“…We showed that knocking down FASN accelerated ATRA-induced differentiation, while inhibition of its enzymatic function by pharmacological inhibitors such as C75 or Orlistat had no effect. Furthermore, we found that FASN expression activates mTOR We further confirmed that EGCG positively impacts on cellular differentiation in additional AML subtypes in vitro (Britschgi et al, 2010;Moradzadeh et al, 2018;Lung et al, 2002). Searching for potential mediators of the positive effects of EGCG observed during ATRA-induced differentiation, we previously found that EGCG induces expression of the Ca 2+ /calmodulin-regulated serine/threonine kinase DAPK2.…”

Section: Discussionsupporting

confidence: 67%

“…Given the fact that APL cells treated with EGCG demonstrated improved response to ATRA therapy, we asked if EGCG can be beneficial to other AML subtypes that are refractory to ATRA treatment. We and others previously demonstrated a positive impact of co-treating HL60 AML cells, a non-APL AML cell line that responds to ATRA, with EGCG and ATRA (Britschgi et al, 2010;Moradzadeh et al, 2018;Lung et al, 2002). Therefore, we tested if ATRA-refractory AML cell lines with different genetic backgrounds, namely MOLM-13 (FLT3-ITD + ) and OCI/AML2 (DNMT3A R635W mutation), would respond to ATRA in combination with EGCG.…”

Section: Lowering Fasn Expression Improves Atra Therapy In Non-apl Ammentioning

confidence: 99%

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Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

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Switzerland 2 TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138 Abstract Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes.Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34 + hematopoietic progenitors in two AML cohorts (n=68, n=203) (p<0.05). Accordingly, FASN levels decreased during ATRA-mediated granulocytic differentiation of APL cells, partially via autophagic degradation. Furthermore, our data suggests that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG), accelerates the differentiation of APL cell lines and significantly resensitized ATRA refractory non-APL AML cells. Decreasing FASN expression reduced mTOR activity and promoted translocation of transcription factor EB (TFEB) to the nucleus. Lysosomal biogenesis was activated, consistent with TFEB transcriptional activation of CLEAR network genes.Together, our data demonstrates that inhibiting FASN expression in combination with ATRA treatment promotes granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells. BioRXiv

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Section: Discussionsupporting

confidence: 67%

Section: Lowering Fasn Expression Improves Atra Therapy In Non-apl Ammentioning

confidence: 99%

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Humbert

Seiler

Mosimann

et al. 2020

Preprint

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“…PML-RARα homodimers worked synchronously with co-repressors and histone deacetylases (HDACs) and consequentially enhanced DNA methylation [29]. EGCG reduced the levels of HDAC1 and PML/RARα in leukemic cells ( Figure 2) [30].…”

Section: Regulation Of Methylation-associated Machinerymentioning

confidence: 99%

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

Farooqi

Pinheiro

Granja

et al. 2020

Cancers

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Decades of research have enabled us to develop a better and sharper understanding of multifaceted nature of cancer. Next-generation sequencing technologies have leveraged our existing knowledge related to intra- and inter-tumor heterogeneity to the next level. Functional genomics have opened new horizons to explore deregulated signaling pathways in different cancers. Therapeutic targeting of deregulated oncogenic signaling cascades by products obtained from natural sources has shown promising results. Epigallocatechin-3-gallate (EGCG) has emerged as a distinguished chemopreventive product because of its ability to regulate a myriad of oncogenic signaling pathways. Based on its scientifically approved anticancer activity and encouraging results obtained from preclinical trials, it is also being tested in various phases of clinical trials. A series of clinical trials associated with green tea extracts and EGCG are providing clues about significant potential of EGCG to mechanistically modulate wide ranging signal transduction cascades. In this review, we comprehensively analyzed regulation of JAK/STAT, Wnt/β-catenin, TGF/SMAD, SHH/GLI, NOTCH pathways by EGCG. We also discussed most recent evidence related to the ability of EGCG to modulate non-coding RNAs in different cancers. Methylation of the genome is also a widely studied mechanism and EGCG has been shown to modulate DNA methyltransferases (DNMTs) and protein enhancer of zeste-2 (EZH2) in multiple cancers. Moreover, the use of nanoformulations to increase the bioavailability and thus efficacy of EGCG will be also addressed. Better understanding of the pleiotropic abilities of EGCG to modulate intracellular pathways along with the development of effective EGCG delivery vehicles will be helpful in getting a step closer to individualized medicines.

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“…However, resistance to these drugs and their toxicity are major problems in the treatment of APL . In the recent years, natural compounds are major subjects for investigating the anticancer drugs with low toxicity and high efficacy . Currently, some of the plant‐derived compounds are widely used for chemotherapy of cancerous patients.…”

Section: Discussionmentioning

confidence: 99%

Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells

Moradzadeh

Ghorbani

Erfanian

et al. 2018

J of Cellular Biochemistry

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Crocetin, the major carotenoid in saffron, exhibits potent anticancer effects. However, the antileukemic effects of crocetin are still unclear, especially in primary acute promyelocytic leukemia (APL) cells. In the current study, the potential antipromyelocytic leukemia activity of crocetin and the underlying molecular mechanisms were investigated. Crocetin (100 µM), like standard anti-APL drugs, all-trans retinoic acid (ATRA, 10 µM) and As O (arsenic trioxide, 50 µM), significantly inhibited proliferation and induced apoptosis in primary APL cells, as well as NB4 and HL60 cells. The effect was associated with the decreased expressions of prosurvival genes Akt and BCL2, the multidrug resistance (MDR) proteins, ABCB1 and ABCC1 and the inhibition of tyrosyl-DNA phosphodiesterase 1 (TDP1), while the expressions of proapoptotic genes CASP3, CASP9, and BAX/BCL2 ratio were significantly increased. In contrast, crocetin at relatively low concentration (10 µM), like ATRA (1 µM) and As O (0.5 µM), induced differentiation of leukemic cells toward granulocytic pattern, and increased the number of differentiated cells expressing CD11b and CD14, while the number of the immature cells expressing CD34 or CD33 was decreased. Furthermore, crocetin suppressed the expression of clinical marker promyelocytic leukemia/retinoic acid receptor-α ( PML/RARα) in NB4 and primary APL cells, and reduced the expression of histone deacetylase 1 ( HDAC1) in all leukemic cells. The results suggested that crocetin can be considered as a candidate for future preclinical and clinical trials of complementary APL treatment.

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Epigallocatechin‐3‐gallate enhances differentiation of acute promyelocytic leukemia cells via inhibition of PML‐RARα and HDAC1

Cited by 25 publications

References 42 publications

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells

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