Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization

Bhat, P. Ishwara; Kriel, Jurgen; Priya, B. S.; Basappa, Basappa; Swamy, S. Nanjunda; Loos, Ben

doi:10.1016/j.bcp.2017.11.021

Cited by 146 publications

(99 citation statements)

References 111 publications

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“…Autophagy is a lysosome-based degradative pathway that plays an essential role in maintaining cellular homeostasis. 42 It has been widely reported that autophagy presents as both a survival mechanism and direct contributor to cell death. Modulating autophagy has recently emerged as a promising therapeutic approach for certain cancer types.…”

Section: Discussionmentioning

confidence: 99%

<p>Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy</p>

Li¹,

Li²,

Jiang³

et al. 2019

IJN

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Background Gadolinium-based nanoparticles (GdNPs) have been used as theranostic sensitizers in clinical radiotherapy studies; however, the biomechanisms underlying the radio-sensitizing effects of GdNPs have yet to be determined. In this study, ultra-small gadolinium oxide nanocrystals (GONs) were employed to investigate their radiosensitizing effects and biological mechanisms in non-small-cell lung cancer (NSCLC) cells under X-ray irradiation. Method and materials GONs were synthesized using polyol method. Hydroxyl radical production, oxidative stress, and clonogenic survival after X-ray irradiation were used to evaluate the radiosensitizing effects of GONs. DNA double-strand breakage, cell cycle phase, and apoptosis and autophagy incidences were investigated in vitro to determine the radiosensitizing biomechanism of GONs under X-ray irradiation. Results GONs induced hydroxyl radical production and oxidative stress in a dose- and concentration-dependent manner in NSCLC cells after X-ray irradiation. The sensitizer enhancement ratios of GONs ranged between 19.3% and 26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of the cells treated with irradiation alone. Addition of 3-methyladenine to the cell medium decreased the incidence rate of autophagy and increased cell survival, supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray irradiation. Conclusion This study examined the biological mechanisms underlying the radiosensitizing effects of GONs on NSCLC cells and presented the first evidence for the radiosensitizing effects of GONs via activation of cytostatic autophagy pathway following X-ray irradiation.

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Section: Discussionmentioning

confidence: 99%

<p>Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy</p>

Li¹,

Li²,

Jiang³

et al. 2019

IJN

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“…The increasing recognition of metabolic dysfunction in cancer cells has shifted the research focus to metabolic modulation‐based adjuvant therapies. One key pathway that anchors metabolite sensing to protein degradation and bioenergetic efficiency is protein degradation through autophagy …”

Section: Introductionmentioning

confidence: 99%

“…One key pathway that anchors metabolite sensing to protein degradation and bioenergetic efficiency is protein degradation through autophagy. 4 Autophagy is a highly controlled lysosome-mediated function in eukaryotic cells, eliminating damaged or aged, long-lived proteins and organelles, such as endoplasmic reticulum, mitochondria or ribosomes. Autophagy plays a crucial role in maintaining cell survival under multiple stresses and restoring cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Yin

Feng

et al. 2019

J Oral Pathology Medicine

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Background The aim of this study was to conduct a comparative evaluation of the expression levels of autophagy markers and proteins of the mammalian target of rapamycin (mTOR) pathway in normal, margin and tumour tissues of patients with oral squamous cell carcinoma (OSCC). Materials and Methods Three regional specimens, including normal, margin and tumour tissues, were collected from 26 patients with OSCC. Western blotting, immunohistochemistry and immunofluorescence staining were performed to detect mTOR, eukaryotic translation initiation factor 4E‐binding protein 1 (4E‐BP1), p70 ribosomal S6 protein kinase (p70S6K) and the corresponding phosphorylated proteins, as well as the light chain 3 (LC3) and sequestosome‐1 (SQSTM1, also known as p62) autophagy indicators. Results LC3‐II, p62, mTOR, phospho‐mTOR, 4E‐BP1 and phospho‐4E‐BP1 were highly expressed in the margin and tumour groups. There were positive correlations between mTOR/phospho‐mTOR, mTOR/4E‐BP1, mTOR/phospho‐4E‐BP1, mTOR/p70S6K, LC3‐II/p62, LC3‐II/p70S6K, p62/4E‐BP1 and p62/phospho‐4E‐BP1 in normal group, while LC3‐II/p62, LC3‐II/mTOR, LC3‐II/4E‐BP1, LC3‐II/phospho‐4E‐BP1, phospho‐4E‐BP1/mTOR, phospho‐4E‐BP1/4E‐BP1 and p62/4E‐BP1 showed positive relationships in margin group; however, in tumour group, only mTOR/phospho‐mTOR, 4E‐BP1/phospho‐4E‐BP1 and phospho‐mTOR/p70S6K showed positive correlations. Conclusion The study suggests that autophagy is impaired in patients with OSCC and impaired autophagy and the mTOR pathway are simultaneously activated in OSCC cells.

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“…These examples highlight the possibility of autosis also occurring in cancer models displaying features of ADCD. Autophagy modulators (both inducers and inhibitors) have proven to sensitize several cancer types to chemotherapy [87,88]. Yet, although therapeutic potential is enormous, clinical trials have remained largely unsuccessful due to the dose-limiting toxicity of autophagy modulators in combination with chemotherapeutics [89][90][91] as well as pharmacological, technical or experimental challenges associated with autophagy control.…”

Section: Autosis Induction As Treatment Modalitymentioning

confidence: 99%

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

2019

Self Cite

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The recent discovery of autosis as a variant of autophagy-dependent cell death has challenged the conventional understanding of cell death and programmed cell death in cellular decision making. In contrast to previous accounts of distinct cell death modalities, autosis occurs with high autophagic activity, in the absence of apoptotic and necrotic markers and yet is not fully regulated by typical autophagy markers. Given the metabolic importance of autophagic responses and the extensive cross-talk with both apoptosis and necrosis signalling, the classical and morphotype-driven characterization of cell death as pre-determined subroutines is being increasingly called into question. Furthermore, the conflicting evidence with regards to cell death induction through autophagy modulation in various cancer models highlights the lack of consensus over the extent to which autophagy assists in cell death ontrol and whether it is capable of being a bona fide lethal process. This review evaluates the evidence and context of autophagy-dependent cell death and delineates the role of an autophagic flux threshold associated with 'lethal' and 'non-lethal' autophagy and its role in autosis control. In doing so, cancer treatment avenues will be explored with regards to precision modulation of tumour autophagic flux to ascertain whether autosis induction may present a novel therapeutic strategy.

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Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization

Cited by 146 publications

References 111 publications

<p>Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy</p>

<p>Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy</p>

Simultaneous activation of impaired autophagy and the mammalian target of rapamycin pathway in oral squamous cell carcinoma

The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

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