Autophagy induction for the treatment of cancer

Pietrocola, Federico; Pol, Jonathan; Vacchelli, Erika; Baracco, Elisa Elena; Lévesque, Sophie; Castoldi, Francesca; Maiuri, Maria Chiara; Madeo, Frank; Kroemer, Guido

doi:10.1080/15548627.2016.1214778

Cited by 54 publications

(59 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Starvation of mice reduces the overall level of protein acetylation in the heart and in the muscle, 21,26 a phenomenon that is related to the known capacity of starvation to deplete acetylCoA 21 and to activate the deacetylase activity of sirtuins. 27,28 Therefore, we investigated the effects of starvation on protein acetylation levels by immunofluorescence staining of permeabilized and fixed leukocytes with an antibody specific for protein containing acetylated lysine residues.…”

Section: Alterations In Protein Acetylation After Starvationmentioning

confidence: 99%

Metabolic effects of fasting on human and mouse blood in vivo

et al. 2017

Self Cite

View full text Add to dashboard Cite

Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes »20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B C puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.

show abstract

Section: Alterations In Protein Acetylation After Starvationmentioning

confidence: 99%

Metabolic effects of fasting on human and mouse blood in vivo

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently Plantinga et al reported a significant association between diffuse LC3-I intensity and LC3-II-positive puncta in non-medullary thyroid cancer patients, and that the LC3-II was closely correlated with clinical response to RAI therapy 35. Although the role of autophagy in thyroid cancer initiation and development is still in debate, proper modulation of autophagy may optimize treatment strategies for DTC patients 55.…”

Section: Discussionmentioning

confidence: 99%

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer

Wei¹,

Sun²,

Shen³

et al. 2017

Theranostics

View full text Add to dashboard Cite

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.

show abstract

“…SERMs including tamoxifen inhibit these enzymes leading to accumulation of sterol precursors—triggering autophagic survival [59]. By delaying apoptosis or DNA damage mechanisms, autophagy can be viewed as an adaptive response to promote the survival of the targeted tumour cells [29, 49, 60]. It has also been postulated that autophagy enables cancer cells to adopt a dormant state [18, 61].…”

Section: Autophagy-mediated Drug Resistance and Cancer Cell Survivalmentioning

confidence: 99%

Autophagy modulation: a prudent approach in cancer treatment?

Bishop

Bradshaw

2018

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Autophagy is a tightly controlled process comprising lysosomal degradation and recycling of cellular proteins and organelles. In cancer, its paradoxical dual role of cytoprotection and cytotoxicity is context-dependent and controversial. Autophagy primarily acts as a mechanism of tumour suppression, by maintenance of genomic integrity and prevention of proliferation and inflammation. This, combined with immune-surveillance capabilities and autophagy's implicated role in cell death, acts to prevent tumour initiation. However, established tumours exploit autophagy to survive cellular stresses in the hostile tumour microenvironment. This can lead to therapy resistance, one of the biggest challenges facing current anti-cancer approaches. Autophagy modulation is an exciting area of clinical development, attempting to harness this fundamental process as an anti-cancer strategy. Autophagy induction could potentially prevent tumour formation and enhance anti-cancer immune responses. In addition, drug-induced autophagy could be used to kill cancer cells, particularly those in which the apoptotic machinery is defective. Conversely, autophagy inhibition may help to sensitise resistant cancer cells to conventional chemotherapies and specifically target autophagy-addicted tumours. Currently, hydroxychloroquine is in phase I and II clinical trials in combination with several standard chemotherapies, whereas direct, deliberate autophagy induction remains to be tested clinically. More comprehensive understanding of the roles of autophagy throughout different stages of carcinogenesis has potential to guide development of novel therapeutic strategies to eradicate cancer cells.

show abstract

Autophagy induction for the treatment of cancer

Cited by 54 publications

References 0 publications

Metabolic effects of fasting on human and mouse blood in vivo

Metabolic effects of fasting on human and mouse blood in vivo

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer

Autophagy modulation: a prudent approach in cancer treatment?

Contact Info

Product

Resources

About