The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia

Zhang, Dongdong; Liu, Yunjiao; 羅, 志偉; Chen, Yanling; Xu, Anjie; Liang, Yuxing; Wu, Balu; Tong, Xiqin; Liu, Xiaoyan; Shen, Hui; Liu, Li; Wei, Yongchang; Zhou, Hai‐Bing; Liu, Yi; Zhou, Fuling

doi:10.1016/j.freeradbiomed.2019.11.013

Cited by 18 publications

(19 citation statements)

References 49 publications

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“…One of these derivatives, termed A-Z2 [for N -(4-(1,3,2-dithiarsinan-2-yl) phenyl)-azelamide], shows stronger activity against TrxR1 activity in acute myeloid leukemia (AML) cell lines than did AZA or arsenicals separately. The compound activates the intrinsic apoptotic pathway by selectively targeting TrxR1/Trx1 and indirectly inhibiting NF-kB; the compound also demonstrated efficacy in vivo against a patient-derived xenograft (PDX) AML model [ 81 ].…”

Section: Preclinical Evidence Of Auranofin Monotherapy Eliciting Anti-cancer Effectsmentioning

confidence: 99%

The gold complex auranofin: new perspectives for cancer therapy

Abdalbari

Telleria

2021

Discov Onc

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Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin–proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.

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Section: Preclinical Evidence Of Auranofin Monotherapy Eliciting Anti-cancer Effectsmentioning

confidence: 99%

The gold complex auranofin: new perspectives for cancer therapy

Abdalbari

Telleria

2021

Discov Onc

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“…In our previous reports on drug screening using a PDX model of HLL, B-NSG mice in the 2.5 Gy group survived beyond 20 days when injected with other HLL cells without malignant gene mutations [28], and B-NSG mice without irradiation survived beyond 31 days when injected with human AML cells separated from a hyperleukocytic AML-M5 patient with NPM1 and DNMT3A mutations [29]. In addition, the B-NSG mice with 1.5 Gy irradiation survived beyond 20 days when injected with human AML cells separated from a hyperleukocytic AML-M5 patient with WT1, DNMT3A and FLT3 mutations [30,31]. The mutational status of AML cells is also a key factor in immunode cient mice for the construction of a PDX model [32,33].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Novel CD34+ Hematopoietic Stem Cell-Derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

Jin

羅

et al. 2021

Preprint

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Hyperleukocytic acute myeloid leukemia (HLL) with high early mortality is difficult to therapy. The related research on HLL is still in its infancy, and the establishment of a patient derived xenograft (PDX) model of HLL has not been fully reported. In this study, we establish a CD34+ hematopoietic stem cell-derived xenograft model of HLL for further exploration. Our findings demonstrated that the leukemia cells were detected in peripheral blood, bone marrow, liver, and spleen tissues in mice after inoculation of patient-derived cells. By performing a comparative analysis of multiple experiments, we found the irradiation doses, injection cell counts, gene abnormal and the survival status of the enrolled patients affected the survival time in mice. We successfully established a novel CD34+ hematopoietic stem cell-derived xenograft model of HLL, which shows great promise for mechanistic research, drug screening, individualized therapy, clinical efficacy assessment and precision medicine in HLL.

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“…In our previous reports on drug screening using a PDX model of HLL, B-NSG mice in the 2.5 Gy group survived beyond 20 days when injected with other HLL cells without malignant gene mutations [29], and B-NSG mice without irradiation survived beyond 31 days when injected with human AML cells separated from a hyperleukocytic AML-M5 patient with NPM1 and DNMT3A mutations [30]. In addition, the B-NSG mice with 1.5 Gy irradiation survived beyond 20 days when injected with human AML cells separated from a hyperleukocytic AML-M5 patient with WT1, DNMT3A and FLT3 mutations [31,32]. The mutational status of AML cells is also a key factor in immunode cient mice for the construction of a PDX model [33,34].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Novel CD34+ Hematopoietic Stem Cell-derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

Jin

Zhang

et al. 2021

Preprint

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BackgroundHyperleukocytic acute myeloid leukemia (HLL) with high early mortality is difficult to therapy. The related research on HLL is still in its infancy, and the establishment of a patient derived xenograft (PDX) model of HLL has not been fully reported, especially the CD34+ hematopoietic stem cell-derived xenograft model of HLL. MethodsUsing the routine blood examination, smear analysis and bone marrow biopsy, flow cytometry, mutation analysis to evaluate the establishment of HLL model. And the correlation between the survival time in mice and in patients was analyzed by a linear regression model with variable selection “entered” with SPSS software.ResultsOur findings demonstrated that the leukocyte counts reached up to 37.35Í109/l, and the immunophenotypes of hCD45+, hCD15+ and hCD33+ cells were detected in peripheral blood (PB) and bone marrow (BM) after inoculation with cells derived from PB for establishment of the HLL PDX model. The same results were demonstrated after inoculation with cells derived from BM of the patient. For the CD34+ hematopoietic stem cell derived xenograft model, the CD34+ hematopoietic stem cells more severely infiltrated the BM, liver and spleen. More importantly, human WT1 and NRAS mutants were detected in the liver, spleen and BM of the mouse. By performing a comparative analysis of multiple experiments, we found that mice receiving a higher irradiation dose of 2.5 Gy and higher injected cell counts derived from PB exhibited a shorter survival time. Furthermore, the constructed model mice injected with NRAS, DNMT3A, FLT3, or NMPM1 gene mutations had shorter survival times. The correlation analysis showed that the survival time in mice was significantly related with the survival status of the enrolled patients. ConclusionsWe successfully established a novel CD34+ hematopoietic stem cell-derived xenograft model of HLL, which shows great promise for mechanistic research, drug screening, individualized therapy, clinical efficacy assessment and precision medicine in HLL.

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The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia

Cited by 18 publications

References 49 publications

The gold complex auranofin: new perspectives for cancer therapy

The gold complex auranofin: new perspectives for cancer therapy

Establishment of a Novel CD34+ Hematopoietic Stem Cell-Derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

Establishment of a Novel CD34+ Hematopoietic Stem Cell-derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

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