Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Kim, Yundeok; Eom, Ju In; Jeung, Hoi Kyung; Jang, Ji Eun; Kim, Jin Seok; Cheong, June Won; Kim, Young Sam; Min, Yoo Hong

doi:10.1016/j.biopha.2015.05.012

Cited by 31 publications

(28 citation statements)

References 40 publications

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“…Anticancer therapies commonly activate prosurvival autophagy, allowing cancer cells to overcome cytotoxic or other stresses induced by the treatment (41). We previously described the involvement of autophagy induction in the resistance of myeloid leukemia cells to the cytosine arabinoside (42). Paradoxically, previous studies have reported that c-Myc activates the unfolded protein response, enhancing cell survival by inducing cytoprotective autophagy; conversely, c-Myc inhibition decreases autophagy in cancer cells (43).…”

Section: Discussionmentioning

confidence: 99%

AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

Jang

Eom

Jeung

et al. 2017

Clinical Cancer Research

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110

102

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Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34CD38 leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations. JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs. These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer. .

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Section: Discussionmentioning

confidence: 99%

AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

Jang

Eom

Jeung

et al. 2017

Clinical Cancer Research

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110

102

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“…Anticancer therapies commonly lead to the activation of prosurvival autophagy, allowing cancer cells to overcome cytotoxicity or other treatment-induced stresses [47]. We previously reported that autophagy induction was involved in the resistance of AML cells to cytosine arabinoside [48] and LSCs to a bromodomain and extraterminal domain inhibitor [33], which provided evidence that autophagy could act as a prosurvival mechanism in AML. Consistently, in this study, we observed a protective autophagic response in LSC-like cells after BIX-01294 treatment.…”

Section: Discussionmentioning

confidence: 95%

PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells

Jang

Eom

Jeung

et al. 2020

J Exp Clin Cancer Res

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Background: The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. Methods:We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34 + CD38 − leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. Results: The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/ NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition.Conclusions: PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.

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“…Antimalarial agents hydroxychloroquine and chloroquine are under investigation in clinical trials for a variety of cancers including glioblastoma multiforme, pancreatic adenocarcinoma, sarcoma, multiple myeloma, melanoma and AML [37]. Hydroxychloroquine induced cell death by inhibiting autophagic degradation in AML cells [38]. Autophagy is a self-degradative intracellular process implicated in both tumor suppression and promotion [39].…”

Section: Antiprotozoalmentioning

confidence: 99%

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

Wojcicki

Kadapakkam

Frymoyer

et al. 2020

Cancers

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Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.

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Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Cited by 31 publications

References 40 publications

AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

AMPK–ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells

PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

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