Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Nitto, Takeaki; Sawaki, Kohei

doi:10.1254/jphs.14r15cp

Cited by 15 publications

(15 citation statements)

References 55 publications

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“…To explain the inconsistency in the expression of fusion protein and cell differentiation on MG132 treatment, the RARα expression was measured in different groups. ATRA facilitated the differentiation of APL cells into mature granulocytes by changing epigenetic modifiers on target genes after binding to the ligandbinding domain at the RARα moiety of the PML-RAR [21]. Hence, the stabilization of RARα is of great importance to the expression of downstream differentiation gene/protein.…”

Section: Discussionmentioning

confidence: 99%

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

Shao

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although the cure rate of acute promyelocytic leukemia (APL) has exceeded 90%, the relapse/refractory APL that resistant to all-trans retinoic acid (ATRA) or ATO was still serious concern. Matrine (MAT) could improve the differentiation ability of ATRA-resistant APL cells. This study aimed to explore how the APL-specific fusion protein was degraded in ATRA-resistant APL with the application of MAT and ATRA. Methods: ATRA-sensitive (NB4) and ATRA-resistant (NB4-LR1) cell lines were used. Nitroblue tetrazolium reduction assay and flow cytometry were used to detect the differentiation ability. The activity of ubiquitin-proteasome and autophagy-mediated pathways in both cells treated with ATRA with or without MAT were compared in protein and mRNA level (Western blot analysis, qRT-PCR), the Fluorescent substrate Suc-LLVY-AMC detection was used to detect the activity of proteasome, and electron microscope for observing autophagosome. MG 132(proteasome inhibitor), rapamycin (autophagy activator), hydroxychloroquine (lysosomal inhibitor) and STI571 [retinoic acid receptor alpha (RARα) ubiquitin stabilizer] were used as positive controls. The effect of MAT was observed in vivo using xenografts. Results: MAT improved the sensitivity of NB4-LR1cells to ATRA treatment, which was consistent with the expression of PML-RARα fusion protein. MAT promoted the ubiquitylation level in NB4-LR1. MG 132 induced the decrease in RARα in both cell lines, and hampered the differentiation of NB4 cells. MAT also promoted the autophagy in NB4-LR1 cells, with an increase in microtubule-associated protein 1 light chain3 (LC3)-II and LC3-II/LC3-I ratio and exhaustion of P62. The expression of LC3II increased significantly in the MAT and ATRA + MAT groups in combination with lysosomal inhibitors. A similar phenomenon was observed in mouse xenografts. MAT induced apoptosis and differentiation. Conclusions: Autophagy and ubiquitin-mediated proteolytic degradation of PML/RARα fusion protein are crucial in MAT-induced differentiation sensitivity recovery of NB4-LR1 cells.

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Section: Discussionmentioning

confidence: 99%

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

Shao

Zhou

et al. 2018

Cell Physiol Biochem

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“…All-trans-retinoic acid (ATRA) is currently the most efficient agent used in differentiation therapy of acute myeloid leukemia (AML). Although higher clinical efficiency in APL patients is achieved by a combination of ATRA with arsenic trioxide (ATO) [ 12 , 36 , 37 ], the development of chemotherapeutic differentiation therapies is still limited. Hence, developing specific agents that can trigger differentiation of leukemic cells along normal hematopoietic lineages has become necessary.…”

Section: Discussionmentioning

confidence: 99%

Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

Liu

Men

et al. 2015

Oncotarget

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All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

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“…Under treatment with all-trans-retinoic acid (ATRA), the NCOR/HDAC complex is dissociated from RAR and the maturation of promyelocytes is restored. Standard protocols combining ATRA with anthracycline-based chemotherapy are demonstrated to guarantee ~70% cure rate (2).…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin in the growth modulation and differentiation of acute myeloid leukemia cells

Liddo

Bridi

Gottardi

et al. 2016

International Journal of Oncology

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Abstract. Adrenomedullin (ADM) is a regulatory peptide endowed with multiple biological effects, including the regulation of blood pressure, cell growth and innate host defence. In the present study, we demonstrated that ADM signaling could be involved in the impaired cellular differentiation of myeloid leukemia cells to mature granulocytes or monocytes by modulating RAMPs/CRLR expression, PI3K/Akt cascade and the ERK/MAPK signaling pathway. When exogenously administered to in vitro cultures of HL60 promyelocytic leukemia cells, ADM was shown to exert a strong proliferative effect with minimal upregulation in the expression level of monocyte antigen CD14. Notably, the experimental inhibition of ADM signaling with inhibitor ADM 22-52 promoted a differentiative stimulation towards monocytic and granulocytic lineages. Moreover, based on the expression of CD31 relative to CD38, we hypothesized that an excess of ADM in bone marrow (BM) niche could increase the transendothelial migration of leukemia cells while any inhibitory event of ADM activity could raise cell retention in hyaluronate matrix by upregulating CD38. Taken into consideration the above evidence, we concluded that ADM and ADM 22-52 could differently affect the growth of leukemia cells by autocrine/paracrine mechanisms and may have clinical relevance as biological targets for the intervention of tumor progression.

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Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Cited by 15 publications

References 55 publications

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

Adrenomedullin in the growth modulation and differentiation of acute myeloid leukemia cells

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