Long term curative effects of sequential therapy with all-trans retinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia

Pei, Renzhi; Cao, Junjie; Ma, Jian; Zhang, Pisheng; Liu, Xuhui; Du, Xiaohong; Chen, Dong; Sha, Keya; Chen, Lieguang; Li, Shuangyue; Wu, Jingyi; Fan, Zhen; Liu, Lin; Ye, Peipei; Tang, Shaohui; Zhang, Bibo

doi:10.1179/102453312x13451850327262

Cited by 15 publications

(6 citation statements)

References 26 publications

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“…The complete remission rate of APL exceeded 90% with the application of all-trans retinoic acid (ATRA), arsenic trioxide (ATO), and anthracycline-based chemotherapy [2]. However, the 7-year cumulative incidence of relapses was reported as 28.6% in APL maintenance with ATRA and daunorubicin [3] and even reached 33% in the ATRA maintenance treatment group [4].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…RA is an effective chemotherapeutic agent for acute promyelocytic leukemia for its transcriptional activation of RXRs (7)(8)(9). RA was also a potent inhibitor on adipocyte differentiation via activation of the nuclear receptor PPARg, a heterodimer with RXR (10).…”

Section: Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

Liu

Chen

Wang

et al. 2015

The American Journal of Clinical Nutrition

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Background: Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. Objective: This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Design: Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor a (RXRa) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Results: Serum RA concentrations in patients with NAFLD (1.42 6 0.47 ng/mL) and NASH (1.14 6 0.26 ng/mL) were significantly lower than those in control subjects (2.70 6 0.52 ng/mL) (P , 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 6 0.52 (n = 28) vs. 2.32 6 0.44 ng/mL (n = 13)], NAFLD [1.61 6 0.37 (n = 29) vs. 1.28 6 0.41 ng/mL (n = 16)], and NASH [1.35 6 0.34 (n = 24) vs. 1.07 6 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRa mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRa mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P , 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRa protein was lower in more severe grades in patients with NAFLD. Conclusion: These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.Am J Clin Nutr 2015;102:130-7.

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“…In the study period, 2 prospective trials of APL (ChiCTR‐TRC‐12002151 and NCT01987297) have been performed in our center. Details of the specific protocols have been provided previously . For the purpose of our analysis, patients were categorized into 2 groups according the front‐line treatment regimens, either intravenous ATO containing (ATO group) or non‐ATO‐containing regimens (non‐ATO group).…”

Section: Methodsmentioning

confidence: 99%

Improved long‐term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide‐based front‐line therapy

Lou

Lu²,

Zhu

et al. 2018

Hematological Oncology

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Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.

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Long term curative effects of sequential therapy with all-trans retinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia

Abstract: We conclude that APL patients may benefit from the use of the combination of ATRA and As(2)O(3) in either remission induction or consolidation/maintenance.

Cited by 15 publications

References 26 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

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

Improved long‐term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide‐based front‐line therapy

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