GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy

Heidari, Nastaran; Hicks, Mark; Harada, Hisashi

doi:10.1038/cddis.2010.53

Cited by 102 publications

(90 citation statements)

References 38 publications

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“…Stimulates obatoclax-induced apoptosis [131] Triggers caspase-3 activation Casp-3, -8, -9 (Beclin-1-C) Enhances IL-3 withdrawal-induced cell death [135] Targets mitochondria Induces Omi and cyt c release…”

Section: Beclin-1 Uncleavedmentioning

confidence: 99%

“…Furthermore, several Atg proteins were shown to trigger cell death and to engage the apoptotic pathway (Table 1). Atg5 was shown to directly bind Fas-associated protein with death domain (FADD), thereby triggering IFN-γ-induced cell death [129]; Atg7 mediates lysosome dysfunctioninduced apoptosis in neural cells [130]; and Beclin-1 stimulates apoptosis in response to the Bcl-2 inhibitor, obatoclax [131]. Moreover, a recent study uncovered the existence of an Atg12-Atg3 conjugation, which sensitizes cells to death downstream of mitochondrial pathways Table 1 List of Atg proteins exerting a pro-apoptotic function…”

Section: Apoptotic Cell Deathmentioning

confidence: 99%

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Autophagy: for better or for worse

et al. 2011

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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

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Section: Beclin-1 Uncleavedmentioning

confidence: 99%

Section: Apoptotic Cell Deathmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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“…Accordingly, an increasing number of reports suggest that there is indeed a complex interplay between autophagy and apoptosis, evidenced by the extensive molecular cross-talk between autophagy-related and apoptosis-related proteins. In this regard, several ATG proteins have been reported to engage the apoptotic pathway (61)(62)(63), whereas depletion of key autophagy regulators or pharmacological interference with autophagy has been shown to mitigate apoptosis (64). Conversely, several apoptotic proteins have been shown to regulate the autophagy process.…”

Section: Discussionmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Protein (pRb)/E2 Promoter Binding Factor 1 (E2F1) Pathway as a Novel Mediator of TGFβ-induced Autophagy

Korah

Canaff

Lebrun

2016

Journal of Biological Chemistry

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TGF␤ is a multifunctional cytokine that regulates cell proliferation, cell immortalization, and cell death, acting as a key homeostatic mediator in various cell types and tissues. Autophagy is a programmed mechanism that plays a pivotal role in controlling cell fate and, consequently, many physiological and pathological processes, including carcinogenesis. Although autophagy is often considered a pro-survival mechanism that renders cells viable in stressful conditions and thus might promote tumor growth, emerging evidence suggests that autophagy is also a tumor suppressor pathway. The relationship between TGF␤ signaling and autophagy is context-dependent and remains unclear. TGF␤-mediated activation of autophagy has recently been suggested to contribute to the growth inhibitory effect of TGF␤ in hepatocarcinoma cells. In the present study, we define a novel process of TGF␤-mediated autophagy in cancer cell lines of various origins. We found that autophagosome initiation and maturation by TGF␤ is dependent on the retinoblastoma tumor suppressor protein/E2 promoter binding factor (pRb/E2F1) pathway, which we have previously established as a critical signaling axis leading to various TGF␤ tumor suppressive effects. We further determined that TGF␤ induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes. Together, our findings reveal that TGF␤ induces autophagy through the pRb/E2F1 pathway and transcriptional activation of autophagy-related genes and further highlight the central relevance of the pRb/E2F1 pathway downstream of TGF␤ signaling in tumor suppression.

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“…Several reports have shown that increased Mcl-1 expression is associated with GC resistance (Holleman et al, 2004;Stam et al, 2010) and it has been demonstrated that Obatoclax treatment can rewww.intechopen.com sensitizes GC-resistant ALL cells (Bonapace et al, 2010). Other results suggest that Obatoclax could be useful as a therapeutic agent against ALL and that the activity and/or the expression of antiapoptotic proteins could be used as a biomarker to determine the appropriate treatment strategy for ALL patients (Heidari et al, 2010). In particular, Bonapace et al have shown that Obatoclax can overcome the resistance to GC through rapid activation of autophagy-dependent necroptosis, which was able to bypass the apoptotic block in the mitochondrion.…”

Section: Apoptosis Modulatorsmentioning

confidence: 99%