Role of autophagy in the progression and suppression of leukemias

Ekiz, H. Atakan; Can, Geylani; Baran, Yusuf

doi:10.1016/j.critrevonc.2011.03.009

Cited by 21 publications

(8 citation statements)

References 121 publications

(118 reference statements)

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“…Either autophagic cytoprotection or autophagic cell death has been shown to be important for the antileukemic effect of different chemotherapeutic agents [6]. Therefore, in addition to apoptosis, we investigated if autophagy was involved in T315-mediated cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Autophagy is a cellular process in which intracellular components are engulfed, digested and recycled via the formation of autophagosomes and autolysosomes, important for cell survival under stress and harmful conditions [6]. This anti-apoptosis function of autophagy has important biological and pathological implications including ischemic injury, cancer therapy and chemoresistance [7].…”

Section: Discussionmentioning

confidence: 99%

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T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

Chiu

Weng

Jadhav

et al. 2016

IJMS

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T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

Chiu

Weng

Jadhav

et al. 2016

IJMS

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“…The myeloid leukemias are a heterogeneous group of diseases characterized by neoplastic cells that infiltrate the blood, bone marrow and other tissues of the hematopoietic system. In previous studies, induction of autophagy was demonstrated to be important for the death of leukemic cells ( 11 – 14 , 38 ), and the induction of autophagy by various drugs, such as imatinib mesylate, arsenic trioxide, everolimus, brevinin-2R and eupalinin A, was attempted. Autophagy may be an important pathway of cell death during various chemotherapeutic modalities, and manipulation of autophagy may be a useful clinical application for targeting multidrug-resistant leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…Although triggering autophagy may be a potential therapeutic strategy to overcome drug resistance, inhibiting autophagy may be another therapeutic strategy to improve the outcome of anticancer treatments. For example, autophagy acts as a prosurvival mechanism and contributes to drug resistance in various types of leukemia ( 38 ). By contrast, inhibition of autophagy was documented to enhance the therapeutic benefit of tyrosine kinase inhibitors in Philadelphia (Ph)-positive leukemias, and the tumor anti-leukemic effect of the histone deacetylase inhibitor, SAHA, was augmented by co-treatment with an autophagy inhibitor ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Enhanced autophagy in cytarabine arabinoside-resistant U937 leukemia cells and its potential as a target for overcoming resistance

Cheong

Kim

Eom

et al. 2016

Molecular Medicine Reports

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Autophagy is a lysosomal degradation mechanism that is essential for cell survival, differentiation, development, and homeostasis. Autophagy protects cells from various stresses, including protecting normal cells from harmful metabolic conditions, and cancer cells from chemotherapeutics. In the current study, a cytarabine arabinoside (Ara-C)-sensitive U937 leukemia cell line and an Ara-C-resistant U937 (U937/AR) cell line were assessed for baseline autophagy activity by investigating the LC3-I conversion to LC3-II, performing EGFP-LC3 puncta, an acidic autophagolysosome assay, and measuring the expression of various autophagy-related genes. The results demonstrated significantly higher autophagic activity in the U937/AR cells compared with the U937 cells, when the cells were cultured with or without serum. Furthermore, an increase in the autophagic activity in starved U937/AR cells was demonstrated, compared with that in the starved U937 cells. Administration of an autophagy inhibitor demonstrated no change in cell death in the two cell lines when cultured with serum, however, it induced cell death regardless of the Ara-C sensitivity when the cell lines were cultured without serum. In addition, the U937 cells demonstrated an Ara-C resistance when cultured without serum. Co-treatment with Ara-C and the autophagy inhibitor significantly induced cell death in the U937/AR and Ara-C-sensitive U937 cells. In conclusion, autophagy serves an important role in protecting U937 cells from Ara-C and in the development of Ara-C resistance. Inhibition of autophagy combined with the Ara-C treatment in the U937 cells augmented the anti-leukemic effect of Ara-C and overcame Ara-C resistance, suggesting that autophagy may be an important therapeutic target to further improve the treatment outcome in patients with acute myeloid leukemia.

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“…The first is that autophagy inhibition leads to increased necrosis rate, which is associated with the inflammatory response and thus cancer development. The second may be rapid accumulation of mutations due to the lack of counteracting the effects of increased oxidative stress by autophagy (25); however, in all cases, autophagy is be easily detected by observing characteristic structures, including the autophagosome and autophagolysosomes (26).…”

Section: Introductionmentioning

confidence: 99%

Lidocaine induces protective autophagy in rat C6 glioma cell line

et al. 2018

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Malignant glioma is the most common type of brain cancer with poor prognosis. Surgical resection, chemotherapy and radiotherapy are the main therapeutic options; however, in addition to their insufficient efficacy, they are associated with the pain experienced by patients. To relieve pain, local anesthetics, such as lidocaine can be used. In the present study, the effects of lidocaine on the C6 rat glioma cell line were investigated. An MTT assay and Annexin V/propidium iodide analysis indicated the increase in the percentage of apoptotic and necrotic cells in response to lidocaine. Furthermore, light microscopy analysis on the ultrastructural level presented the occurrence of vacuole-like structures associated with autophagy, which was supported by the analysis of autophagy markers (microtubule-associated protein 1A/1B-light chain 3, acridine orange and Beclin-1). Additionally, reorganization of the cytoskeleton was observed following treatment with lidocaine, which serves an important role in the course of autophagy. To determine the nature of autophagy, an inhibitor, bafilomycin A1 was applied. This compound suppressed the fusion of autophagosomes with lysosomes and increased the percentage of apoptotic cells. These results demonstrated that lidocaine may induce cytoprotective autophagy and that manipulation of this process could be an alternative therapeutic strategy in the treatment of cancer.

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Role of autophagy in the progression and suppression of leukemias

Cited by 21 publications

References 121 publications

T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

Enhanced autophagy in cytarabine arabinoside-resistant U937 leukemia cells and its potential as a target for overcoming resistance

Lidocaine induces protective autophagy in rat C6 glioma cell line

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