Disulfiram/cytarabine eradicates a subset of acute myeloid leukemia stem cells with high aldehyde dehydrogenase expression

Yang, Wanfang; Xie, Juan; Hou, Ruixia; Chen, Xiuhua; Xu, Zhifang; Tan, Yanhong; Ren, Fanggang; Zhang, Yaofang; Xu, Jing; Chang, Jianmei; Wang, Hongwei

doi:10.1016/j.leukres.2020.106351

Cited by 13 publications

(6 citation statements)

References 38 publications

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“…We had specifically chosen chemotherapeutics with varying involvement of ABC transporters and ALDH in resistance pathways (Table 1) to explore their relative efficacy. Interestingly, resistance patterns of the partially effective drugs (CY, MTX, and ARA-C) diverge (8,(12)(13)(14)(20)(21)(22)(23), but may explain why each had differing effects on T-cell subset activation, proliferation, differentiation, and recovery kinetics. Yet, resistance patterns are not very dissimilar for the ineffective drugs compared with the effective drugs (Table 1) (8,(12)(13)(14)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), suggesting either a small therapeutic index to effectively prevent GVHD or that the cellular impact of these drugs and/or their metabolism may be more complicated than we currently appreciate.…”

Section: Discussionmentioning

confidence: 99%

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation

et al. 2022

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Post-transplantation cyclophosphamide (PTCy) reduces the incidence and severity of graft-versus-host disease (GVHD), thereby improving the safety and accessibility of allogeneic hematopoietic cell transplantation (HCT). We have shown that PTCy works by inducing functional impairment and suppression of alloreactive T cells. We also have identified that reduced proliferation of alloreactive CD4+ T cells at day +7 and preferential recovery of CD4+CD25+Foxp3+ regulatory T cells (Tregs) at day +21 are potential biomarkers associated with optimal PTCy dosing and timing in our B6C3F1→B6D2F1 MHC-haploidentical murine HCT model. To understand whether the effects of PTCy are unique and also to understand better the biology of GVHD prevention by PTCy, here we tested the relative impact of cyclophosphamide compared with five other optimally dosed chemotherapeutics (methotrexate, bendamustine, paclitaxel, vincristine, and cytarabine) that vary in mechanisms of action and drug resistance. Only cyclophosphamide, methotrexate, and cytarabine were effective in preventing fatal GVHD, but cyclophosphamide was superior in ameliorating both clinical and histopathological GVHD. Flow cytometric analyses of blood and spleens revealed that these three chemotherapeutics were distinct in constraining conventional T-cell numerical recovery and facilitating preferential Treg recovery at day +21. However, cyclophosphamide was unique in consistently reducing proliferation and expression of the activation marker CD25 by alloreactive CD4+Foxp3- conventional T cells at day +7. Furthermore, cyclophosphamide restrained the differentiation of alloreactive CD4+Foxp3- conventional T cells at both days +7 and +21, whereas methotrexate and cytarabine only restrained differentiation at day +7. No chemotherapeutic selectively eliminated alloreactive T cells. These data suggest that constrained alloreactive CD4+Foxp3- conventional T-cell numerical recovery and associated preferential CD4+CD25+Foxp3+ Treg reconstitution at day +21 may be potential biomarkers of effective GVHD prevention. Additionally, these results reveal that PTCy uniquely restrains alloreactive CD4+Foxp3- conventional T-cell proliferation and differentiation, which may explain the superior effects of PTCy in preventing GVHD. Further study is needed to determine whether these findings also hold true in clinical HCT.

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Section: Discussionmentioning

confidence: 99%

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation

et al. 2022

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“…DSF has been used clinically for decades as an alcohol-abuse drug and plays a role in the treatment of other diseases such as cataract, obesity, myelodysplastic syndrome, leukemia, acquired immunodeficiency syndrome, Alzheimer's disease, etc. (Vassar et al, 1999;Nagai and Ito, 2014;Elliott et al, 2015;Hassani et al, 2018;Reinhardt et al, 2018;Meggyesy et al, 2020;Yang et al, 2020;Zha et al, 2021). DSF is one of the older drugs that have been found to have anticancer and anti-inflammatory effects, and the effects on inflammation manifest as follows: ① inhibition of pyroptosis; ② inhibition of ROS; ③ inhibition of angiogenesis.…”

Section: Prospectivementioning

confidence: 99%

Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

Chen

Chengqing

et al. 2022

Front. Pharmacol.

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Disulfiram has been used clinically for decades as an anti-alcoholic drug. Recently, several studies have demonstrated the anti-inflammatory effects of disulfiram and its metabolism, which can alleviate the progression of inflammation in vivo and in vitro. In the current study, we summarize the anti-inflammatory mechanisms of disulfiram and its metabolism, including inhibition of pyroptosis by either covalently modifying gasdermin D or inactivating nod-like receptor protein 3 inflammasome, dual effects of intracellular reactive oxygen species production, and inhibition of angiogenesis. Furthermore, we review the potential application of disulfiram and its metabolism in treatment of inflammatory disorders, such as inflammatory bowel disease, inflammatory injury of kidney and liver, type 2 diabetes mellitus, sepsis, uveitis, and osteoarthritis.

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“…Disulfiram does not prevent the processing of IL-1β or GSDMD but exclusively blocks the formation of the pore and, thus, pyroptosis and the release of inflammatory cytokines after activation of the NLRP3 inflammasome [104]. Although its potential to prevent pyroptosis was discovered only recently, it has been known for some time that Disulfiram has antitumor activity in multiple types of tumors, including hematological disorders such as AML [124][125][126][127] and ALL [128].…”

Section: Mcc950mentioning

confidence: 99%

The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

Urwanisch

Luciano

Horejs‐Hoeck

2021

IJMS

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Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.

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Disulfiram/cytarabine eradicates a subset of acute myeloid leukemia stem cells with high aldehyde dehydrogenase expression

Cited by 13 publications

References 38 publications

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation

Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

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