Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies

Grandér, Dan; Kharaziha, Pedram; Laane, Edward; Pokrovskaja, Katja; Panaretakis, Theocharis

doi:10.4161/auto.5.8.10122

Cited by 64 publications

(48 citation statements)

References 8 publications

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“…Notably, autophagic cell death has been implicated as a mechanism by which certain antineoplastic agents generate their antitumor activities. Previous work has established that autophagy mediates cell death of acute lymphoblastic leukemia cells by dexamethasone (32,33), promotes differentiation of K562 erythroleukemia cells (34), promotes cell death by histone deacetylase inhibitors in chondrosarcoma cell lines (35), and may constitute a key mechanism by which rapamycin and other mTOR inhibitors promote generation of antitumor responses (36,37).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Goussetis

Altman

Glaser

et al. 2010

Journal of Biological Chemistry

117

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Arsenic trioxide (As 2 O 3 ) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As 2 O 3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As 2 O 3 appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As 2 O 3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As 2 O 3 on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As 2 O 3 and possibly other heavy metal derivatives. Arsenic trioxide (As 2 O 3 )2 is a metalloid that exhibits potent antineoplastic effects in vitro and in vivo (1-3). This arsenic derivative induces apoptosis and suppresses the growth of various types of malignant cells of diverse origin in vitro (1-3). Different mechanisms by which As 2 O 3 promotes cell death of target cells have been extensively studied and described (reviewed in Refs. 1-3). As 2 O 3 -dependent generation of reactive oxygen species leads to activation of pro-apoptotic pathways in different types of cells (1-3). In addition, there is evidence for mechanisms involving As 2 O 3 -dependent cell typespecific targeting of malignant cells with distinct molecular abnormalities (reviewed in Ref.3). For instance, there is evidence for As 2 O 3 -dependent specific targeting of cells expressing AML1/MDS1/EVI1 involving degradation of the abnormal fusion protein (4), evidence for arsenic-dependent BCR-ABL ubiquitination and proteasomal degradation (5), and eradication of leukemia-initiating cells in acute promyelocytic leukemia via As 2 O 3 -inducible PML-RAR␣ degradation (6).Despite extensive research over the years, the precise mechanisms of action of arsenic trioxide in malignant cells are not well understood. In particular, the specific cellular events that account for differential sensitivity of malignant cells to As 2 O 3 remain to be precisely defined. Notably, arsenic trioxide treatment induces responses in patients with acute promyelocytic leukemia in vivo (7,8), and it is an agent approved by the United States Food and Drug Administration for the treatment of this leukemia. The unusually high sensitivity of acute promyelocytic leukemia cells to the effects of arsenic trioxide likely reflects the requirement of lower As 2 O 3 concentrations for induction of leukemic cell differentiation seen in these cells versus apoptotic cell death (3), but other mechanisms may be involved as well.Autophagy is a cell death mechani...

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Section: Discussionmentioning

confidence: 99%

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Goussetis

Altman

Glaser

et al. 2010

Journal of Biological Chemistry

117

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“…[90][91][92] Second, autophagy appears to be responsible for the death of some cancer cells (especially when they lack essential apoptotic modulators like BAX and BAK or caspases) 93,94 that respond to a selected panel of chemotherapeutic agents in vitro. 95,96 Nonetheless, in most known cases, autophagy constitutes a cytoprotective response activated by dying cells in the attempt to cope with stress, and its inhibition accelerates, rather than prevents, cell death. 97 Several methods may be used to determine whether the autophagic pathway is activated above baseline levels in the context of the cellular demise.…”

Section: Definition Of 'Autophagic Cell Death'mentioning

confidence: 99%

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

et al. 2011

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proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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“…For detailed information on experimental procedures we refer readers to various protocols that have been published elsewhere. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] Collectively, we propose the following guidelines for measuring various aspects of selective and nonselective autophagy in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies

Cited by 64 publications

References 8 publications

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Autophagy Is a Critical Mechanism for the Induction of the Antileukemic Effects of Arsenic Trioxide

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Guidelines for the use and interpretation of assays for monitoring autophagy

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