Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide in acute myeloid leukemia cells: Novel synergistic mechanism via the mediation of reactive oxygen species

Mesbahi, Yashar; Zekri, Ali; Ghaffari, Seyed H.; Tabatabaie, Parvaneh Sadat; Ahmadian, Shahin; Ghavamzadeh, Ardeshir

doi:10.1016/j.ejphar.2018.07.010

Cited by 29 publications

(17 citation statements)

References 53 publications

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“…In addition to being the major sites for biosynthesis and energy supply, mitochondria initiate apoptotic signalling in AML cells triggered by chemotherapeutic agents, which includes anti‐apoptotic BCL2, BCL‐xL (also termed BCL2L1) and MCL1, and pro‐apoptotic BAX, BAK (BAK1) and cytochrome c, as well as ROS (Indran et al , ). Induction of ROS is a critical event regulating AML apoptosis induced by chemotherapeutic agents, such as arsenic trioxide, parthenolide (PTL) and Ara‐C (Guzman et al , ; Schimmer, ; Mesbahi et al , ). Sophisticated regulation of ROS level is important for both cell apoptosis and cellular homeostasis, especially for LSCs.…”

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confidence: 99%

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Liu

et al. 2019

Br J Haematol

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Summary Acute myeloid leukaemia (AML) cells possess metabolism profiles, such as higher rates of oxidative phosphorylation and dependence on fatty acid oxidation for survival, and are dependent on the sophisticated regulation of reactive oxygen species (ROS) generation for survival, drug resistance and stemness maintenance. We found that sensitivity of primary AML cells to cytarabine correlated with SOD2 acetylation and the ability of the drug to induce mitochondrial ROS. The SOD2 deacetylase, SIRT3, protected AML cells from chemotherapy as shown by inhibited apoptosis via inhibited drug‐induced production of mitochondrial ROS. SIRT3 significantly decreased nicotinamide adenine dinucleotide phosphate (NADP)/reduced NADP ratio and increased reduced glutathione/oxidized glutathione ratio. Furthermore, SIRT3 enhanced oxidative phosphorylation (OxPhos) in AML cells under both basic and cytarabine‐treated conditions. A xenograft mouse model showed that SIRT3 overexpressing AML cells and patient‐derived xenograft mice bearing high SIRT3 deacetylase activity were more resistant to chemotherapy in vivo. SIRT3 inhibitor displayed synergy with cytarabine to ablate AML cells in vitro and in mouse models. Taken together, our study showed that SIRT3 is capable of reprograming mitochondrial metabolism towards OxPhos and downregulating ROS generation, which contribute to the chemoresistance of AML cells. SIRT3 can be utilized as a potential therapeutic target to improve the anti‐leukaemic efficacy of standard chemotherapeutic agents for AML.

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confidence: 99%

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Liu

et al. 2019

Br J Haematol

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“…Buthioninesulfoximine (BSO) has been identified to halt GSH production and is being increasingly studied owing to its high sensitivity [158,159,160]. ATO (Arsenic trioxide) and BSO administration in acute promyelocytic leukemia (APL) was reported to synergistically reduce GSH levels thereby inducing apoptosis [161,162,163,164]. Similarly, copper N -glycinate (CuNG), a copper derivative, has been illustrated to target GSH in Ehrlich ascites carcinoma and stimulate ROS production [164,165,166].…”

Section: Role Of Ros In Cancer Cell Killingmentioning

confidence: 99%

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

et al. 2019

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Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

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“…Excessive production of ROS is a common feature of cancer. In leukemia, ROS are known to cause DNA damage (5) and also promote proliferation (6)(7)(8). We previously showed that >60% of AML patients exhibited elevated levels of extracellular superoxide and H 2 O 2 which correlated with NOX2 expression (6).…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species Drive Proliferation in Acute Myeloid Leukemia via the Glycolytic Regulator PFKFB3

et al. 2020

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Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide in acute myeloid leukemia cells: Novel synergistic mechanism via the mediation of reactive oxygen species

Cited by 29 publications

References 53 publications

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

Reactive Oxygen Species Drive Proliferation in Acute Myeloid Leukemia via the Glycolytic Regulator PFKFB3

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