Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome‐positive acute lymphoblastic leukaemia

Wang, Tao; Cheng, Cheng; Peng, Lijun; Gao, Meng-Qing; Xi, Meng-Ping; Rousseaux, Sophie; Khochbin, Saadi; Wang, Jin; Mi, Jian-Qing

doi:10.1111/jcmm.13436

Cited by 9 publications

(4 citation statements)

References 30 publications

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“…These findings further strengthen the contention that AMPK activation impacts on the UPR, leading to increased vulnerability to ER stress in ALL cells. Other strategies aimed to unleash proapoptotic UPR in ALL cells involved the use of Pevonedistat ® (Takeda Oncology, Cambridge, MA, USA), an inhibitor of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme that targets E3 cullin-RING ligases-dependent proteasomal protein degradation [150]; of CX-4945, an inhibitor of casein kinase 2 (CK2) signaling [151], also in combination with bortezomib [152]; of the natural acyclic sesquiterpene alcohol, farnesol [153]; of sphingosine kinase inhibitors [154]; of a phosphine copper(I) complex [Cu(thp)4][PF6] [155]; of a combination of ATO and dasatinib that was effective in Ph + B-ALL cells [156]; of epigallocatechin gallate, a green tea extract, that binds to the ATP-binding site of GRP78, thereby leading to a conformational conversion into its inactive oligomeric form [123]. All these studies demonstrated that ALL cells are prone to ER stress/UPR-mediated apoptosis via a variety of signaling pathways/mechanisms.…”

Section: Therapeutic Strategies For B-all and T-allmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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Section: Therapeutic Strategies For B-all and T-allmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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“…Sustained JNK activation can induce apoptosis. [ 20 , 21 ] To detect the apoptotic roles of JNK signaling pathways in BLIN-1 cells, we used the specific JNK inhibitor SP600125 to block JNK phosphorylation and its downstream signaling [ 22 ]. The results showed that 40 μM SP600125 blocks the increase in C-MYC expression and PARP cleavage induced by CpG 685 for 24 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

Bai

Han²,

Chen³

et al. 2023

J Transl Med

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Background The prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown. Methods We discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples. Results High expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation. Conclusion TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph− B-ALL patients with C-MYC overexpression and without BAX deletion. CpG 685 may also serve as an effective combinational therapy against Ph+ B-ALL.

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“…The miR‐214 level was significantly lower in coronary artery disease patients compared with that in controls, which may be a biomarker for alerting severe coronary artery disease 24 . Also, miR‐214‐3p was downregulated in HAECs stimulated with ox‐LDL 25,26 …”

Section: Discussionmentioning

confidence: 95%

LncRNA Miat knockdown alleviates endothelial cell injury through regulation of miR‐214‐3p/Caspase‐1 signalling during atherogenesis

et al. 2021

Clin Exp Pharma Physio

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Atherosclerosis is a common problem in healthy people around the world. Long noncoding RNAs (lncRNAs) play important roles in atherosclerosis. Myocardial infarction‐associated transcript (Miat) is a cardiovascular disease‐associated lncRNA. Its role and mechanism in atherosclerosis is still not fully clarified. Our study aims to explore the role and mechanism of lncRNA Miat in atherosclerosis. The atherosclerosis models were established both in vitro and in vivo. Real‐time PCR was used to measure the expression of lncRNA Miat, miR‐214, Caspase‐1 and IL‐1β. Western blot was performed to detect the protein expression of Caspase‐1. CCK‐8 assay, Tunel staining, and flow cytometry analysis were conducted to detect proliferation and apoptosis of human aortic endothelial cells (HAECs), respectively. Oil red O staining and HE staining were used to evaluated the histological changes of the aorta. The results found that lncRNA Miat was upregulated in ox‐LDL‐induced atherosclerosis model in vitro. The inhibition of lncRNA Miat protects against ox‐LDL‐induced HAEC injury, presented as increased cell viability and decreased apoptosis. LncRNA Miat and miR‐214 has binding site, and CASP1, which encodes Caspase‐1, is a target of miR‐214. The downregulation of lncRNA Miat increased the expression of miR‐214‐3p and decreased the expression of Caspase‐1, as well as its downstream molecule IL‐1β in HAECs. However, the inhibition of miR‐214‐3p attenuated the effect of lncRNA Miat downregulation on HAECs. Furthermore, the downregulation of lncRNA Miat alleviated atherosclerosis in ApoE‐deficient mice. Correspondingly, the expression of miR‐214‐3p was upregulated and Caspase‐1 was downregulated after knockdown of lncRNA Miat. In conclusion, downregulation of lncRNA Miat exerts a protective effect against atherosclerosis through the regulation miR‐214‐3p/Caspase‐1 signalling pathway. Therefore, the inhibition of lncRNA Miat expression may be an effective strategy in the treatment of atherosclerosis.

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Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome‐positive acute lymphoblastic leukaemia

Cited by 9 publications

References 30 publications

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

LncRNA Miat knockdown alleviates endothelial cell injury through regulation of miR‐214‐3p/Caspase‐1 signalling during atherogenesis

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