Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

Baquero, Pablo; Dawson, Amy; Mukhopadhyay, Arunima; Kuntz, Elodie M.; Mitchell, Rebecca; Olivares, O. Porta; Ianniciello, Angela; Scott, Mary T.; Dunn, Kirsty; Nicastri, Michael C.; Winkler, Jeffrey D.; Michie, Alison M.; Ryan, Kevin M.; Halsey, Christina; Gottlieb, Eyal; Keaney, Erin P.; Murphy, Leon O.; Amaravadi, Ravi K.; Holyoake, Tessa L.; Helgason, G. Vignir

doi:10.1038/s41375-018-0252-4

Cited by 100 publications

(95 citation statements)

References 44 publications

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“…Mice lacking FOXO3A show abnormally high ROS levels, impaired leukaemia initiating capacity and myeloproliferation . Similarly, recent results from in vivo studies indicate that potent lysosomal inhibition drives LSCs out of quiescence leading to an expansion of myeloid progenitors . In addition, these results are in line with previous studies in normal HSCs, showing that autophagy deficiency increases oxidative stress and rapidly reduces the stem cell pool .…”

Section: Role and Regulation Of Autophagy In CML And Lscssupporting

confidence: 87%

“…In CML, the expression of ATG genes has been shown to be upregulated in more primitive populations compared to more mature cells . In line with this, our results obtained from leukaemic mice expressing GFP‐LC3 revealed that LSCs have higher autophagy levels compared to more differentiated cells . Similarly, Warr et al .…”

Section: Role and Regulation Of Autophagy In CML And Lscssupporting

confidence: 86%

“…These data suggest that BCR‐ABL may regulate autophagy at a transcriptional level in CML progenitor cells; however, since autophagy is a very dynamic process, which can be rapidly regulated by environmental conditions, further experiments measuring the expression of ATG genes following TKI treatment at different time points are required to support this conclusion. In this regard, in vivo models have recently been generated to measure autophagy flux, using mice expressing the autophagy marker LC3 tagged with GFP . Using this system, our data demonstrate increased autophagy flux in the stem/progenitor cells of BCR‐ABL‐harbouring mice compared to their wild‐type counterparts, with the former showing increased sensitivity to autophagy inhibitors .…”

Section: Role and Regulation Of Autophagy In CML And Lscsmentioning

confidence: 82%

“…Lys05 is a dimeric analogue of HCQ, which has shown 3‐ to 10‐fold more potent effects than HCQ in cancer cell lines. Our recent data show that Lys05 achieves autophagy inhibition in LSCs and effectively sensitizes them to TKIs in vitro and in vivo . Importantly, combination of TKI and HCQ did not add any effects to TKI as a single treatment on LSCs survival.…”

Section: Targeting Therapy‐resistant CML Cells With Second‐generationmentioning

confidence: 84%

“…In this regard, in vivo models have recently been generated to measure autophagy flux, using mice expressing the autophagy marker LC3 tagged with GFP . Using this system, our data demonstrate increased autophagy flux in the stem/progenitor cells of BCR‐ABL‐harbouring mice compared to their wild‐type counterparts, with the former showing increased sensitivity to autophagy inhibitors . Further utilization of this system will provide a suitable model to study the regulation of autophagy in CML LSCs at both transcriptional and post‐translational levels.…”

Section: Role and Regulation Of Autophagy In CML And Lscsmentioning

confidence: 86%

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Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).

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Section: Role and Regulation Of Autophagy In CML And Lscssupporting

confidence: 87%

Section: Role and Regulation Of Autophagy In CML And Lscssupporting

confidence: 86%

Section: Role and Regulation Of Autophagy In CML And Lscsmentioning

confidence: 82%

Section: Targeting Therapy‐resistant CML Cells With Second‐generationmentioning

confidence: 84%

Section: Role and Regulation Of Autophagy In CML And Lscsmentioning

confidence: 86%

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Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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Effects of different autophagy inhibitors on sensitizing KG‐1 and HL‐60 leukemia cells to chemotherapy

et al. 2020

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A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well-known inhibitors of autophagy (as 3-MA, BafA1, and HCQ) in leukemia KG-1 and HL-60 cells exposed to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC-3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG-1 cells compared to HL-60 cell line. This study showed the involvement of autophagy during the treatment of KG-1 and HL-60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG-1 cells.

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Lys05 induces lysosomal membrane permeabilization and increases radiosensitivity in glioblastoma

Zhou

Guo

Zhang

et al. 2019

J of Cellular Biochemistry

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Glioblastoma (GBM) is one of the most malignant primary brain tumors and its prognosis is very poor. Lysosome‐dependent cell death is mainly caused by lysosomal membrane permeabilization (LMP), a process in which the lysosome loses its membrane integrity and lysosomal contents are released into the cytosol. Lysosomotropic agent, a kind of compound that selectively accumulates in the lysosomes, is one of the most important inducers of LMP. As a newly‐synthetic lysosomotropic agent, Lys05 showed efficient autophagy inhibiting and antitumor effect. But its mechanisms are not well illustrated. Here, we studied whether Lys05 has antiglioma activity. We found that Lys05 decreased cell viability and reduced cell growth of glioma U251 and LN229 cells. After Lys05 treatment, autophagic flux is inhibited and lysosome function is impaired. We also found that Lys05 caused LMP and mitochondrial depolarization. Finally, Lys05 increased radiosensitivity in an LMP‐dependent manner. For the first time, our findings indicate that LMP contributes to radiosensitivity in GBM cells. Therefore, LMP inducer, Lys05 might be a promising compound in the treatment of GBM cells.

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Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

Cited by 100 publications

References 44 publications

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

Effects of different autophagy inhibitors on sensitizing KG‐1 and HL‐60 leukemia cells to chemotherapy

Lys05 induces lysosomal membrane permeabilization and increases radiosensitivity in glioblastoma

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