Autophagy as a pharmacological target in hematopoiesis and hematological disorders

Orsini, Marion; Morceau, Franck; Dicato, Mario; Diederich, Marc

doi:10.1016/j.bcp.2018.04.007

Cited by 12 publications

(16 citation statements)

References 211 publications

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“…We found that AC-73 inhibits leukemic cell proliferation by suppressing the ERK/STAT3 activation pathway, known to play a role in AML cell proliferation and survival, 22 but also by activating autophagy, an essential phenomenon for hematopoietic stem cell (HSC) maintenance, resistance to stress, survival and differentiation, the machinery of which might be disrupted in AMLs. 23–25 Next, we analyzed whether AC-73 enhanced the sensitivity of leukemic cells to conventional chemotherapeutic agents. We used arabinosylcytosine (Ara-C), one of the most active cytotoxic agents in myeloid leukemia, and arsenic trioxide (ATO), an active anti-proliferative agent used in the treatment of patients with acute promyelocytic leukemia (APL) (AML-M3) 1,2,26 [although with low efficacy in AML lacking the t(15;17) translocation], and also an inducer of autophagy.…”

Section: Introductionmentioning

confidence: 99%

The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

et al. 2018

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CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematologic target and whether its inhibitor AC-73 may be used in leukemia therapy may reveal an alternative treatment strategy in patients with acute myeloid leukemia (AML). We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with AML. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. We demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy by enhancing leukemic cell sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of AML and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.

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Section: Introductionmentioning

confidence: 99%

The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

et al. 2018

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“…Macroautophagy, which is the most studied type of autophagy, involves the activation of an autophagy receptor, LC3, required for the degradation of cellular contents. Crucial steps such as phagophore formation, elongation, and fusion with a lysosome lead to the formation of auto-phagolysosomes [25]. An increase of vacuoles in the cytoplasm was observed by Diff-Quik staining and TEM images after petromurin C treatment.…”

Section: Discussionmentioning

confidence: 95%

Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML: Synergy with Gilteritinib

Song

Orlikova-Boyer

et al. 2020

Marine Drugs

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Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show in this study that petromurin C, which was isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether, our results provide preliminary indications that petromurin C provides anti-leukemic effects alone or in combination with gilteritinib.

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“…The targeted substrates of selective autophagy can be diverse, and depending on the nature of the organelles, proteins or lipids can be used as targets [47]. Therapeutic approaches modulating autophagic processes (either inhibiting or inducing these processing) are gaining interest and have been proposed as strategies for the treatment of various hematological disorders [48].…”

Section: Induction Of Mitophagymentioning

confidence: 99%

Operation of mitochondrial machinery in viral infection-induced immune responses

Lai

Luo

2018

Biochemical Pharmacology

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Mitochondria have been recognized as ancient bacteria that contain evolutionary endosymbionts. Metabolic pathways and inflammatory signals interact within mitochondria in response to different stresses, such as viral infections. In this commentary, we address several interesting questions, including (1) how do mitochondrial machineries participate in immune responses; (2) how do mitochondria mediate antiviral immunity; (3) what mechanisms involved in mitochondrial machinery, including the downregulation of mitochondrial DNA (mtDNA), disturbances of mitochondrial dynamics, and the induction of mitophagy and regulation of apoptosis, have been adopted by viruses to evade antiviral immunity; (4) what mechanisms involve the regulation of mitochondrial machineries in antiviral therapeutics; and (5) what are the potential challenges and perspectives in developing mitochondria-targeting antiviral treatments? This commentary provides a comprehensive review of the roles and mechanisms of mitochondrial machineries in immunity, viral infections and related antiviral therapeutics.

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Autophagy as a pharmacological target in hematopoiesis and hematological disorders

Cited by 12 publications

References 211 publications

The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells

Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML: Synergy with Gilteritinib

Operation of mitochondrial machinery in viral infection-induced immune responses

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