Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

Bullova, Petra; Cougnoux, Antony; Abunimer, Luma; Kopáček, Juraj; Pastoreková, Silvia; Pacák, Karel

doi:10.18632/oncotarget.9643

Cited by 12 publications

(15 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concerning these data, it seems that a weak deleterious effect of hypoxia, when combined with other pro-apoptotic factor(s), may represent a decisive element leading to pancreatic β-cell death. Potentiation of the cytotoxic effect of various agents due to hypoxia was published in other cell types [21,22]. We have also shown that hypoxia strongly decreased the protective effect of unsaturated OA against the pro-apoptotic effect of saturated SA.…”

Section: Discussionsupporting

confidence: 71%

Hypoxia Modulates Effects of Fatty Acids on NES2Y Human Pancreatic β-cells

Šrámek

Němcová‐Fürstová

Polàk

et al. 2019

IJMS

View full text Add to dashboard Cite

Saturated fatty acids (FAs) induce apoptosis in the human pancreatic NES2Y β-cell line while unsaturated FAs have nearly no detrimental effect. Moreover, unsaturated FAs are capable of inhibiting the pro-apoptotic effect of saturated FAs. Hypoxia is also known to have deleterious effects on β-cells function and viability. In the present study, we have tested the modulatory effect of hypoxia on the effect of FAs on the growth and viability of the human pancreatic NES2Y β-cells. This study represents the first study testing hypoxia effect on effects of FAs in pancreatic β-cells as well as in other cell types. We showed that hypoxia increased the pro-apoptotic effect of saturated stearic acid (SA). Endoplasmic reticulum stress signaling seemed to be involved while redistribution of FA transporters fatty acid translocase/cluster of differentiation 36 (FAT/CD36) and fatty acid-binding protein (FABP) do not seem to be involved in this effect. Hypoxia also strongly decreased the protective effect of unsaturated oleic acid (OA) against the pro-apoptotic effect of SA. Thus, in the presence of hypoxia, OA was unable to save SA-treated β-cells from apoptosis induction. Hypoxia itself had only a weak detrimental effect on NES2Y cells. Our data suggest that hypoxia could represent an important factor in pancreatic β-cell death induced and regulated by FAs and thus in the development of type 2 diabetes mellitus.

show abstract

Section: Discussionsupporting

confidence: 71%

Hypoxia Modulates Effects of Fatty Acids on NES2Y Human Pancreatic β-cells

Šrámek

Němcová‐Fürstová

Polàk

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…GFAP density used the “moments” thresholding method at 95% for the measurement. Microglia projection length was measured using the built-in measurement tool and scaling to convert pixel to μm as previously described [22]. Purkinje cells were counted by measuring the number of calbindin positive cell bodies with a recognizable dendritic tree or axonal projection remaining within a given cerebellar lobule.…”

Section: Methodsmentioning

confidence: 99%

Necroptosis inhibition as a therapy for Niemann-Pick disease, type C1: Inhibition of RIP kinases and combination therapy with 2-hydroxypropyl-β-cyclodextrin

Cougnoux¹,

Clifford²,

Salman³

et al. 2018

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Niemann-Pick disease, type C1 (NPC1) is an inborn error of metabolism that results in endolysosomal accumulation of unesterified cholesterol. Clinically, NPC1 manifests as cholestatic liver disease in the newborn or as a progressive neurogenerative condition characterized by cerebellar ataxia and cognitive decline. Currently there are no FDA approved therapies for NPC1. Thus, understanding the pathological processes that contribute to neurodegeneration will be important in both developing and testing potential therapeutic interventions. Neuroinflammation and necroptosis contribute to the NPC1 pathological cascade. Receptor Interacting Protein Kinase 1 and 3 (RIPK1 and RIPK3), are protein kinases that play a central role in mediating neuronal necroptosis. Our prior work suggested that pharmacological inhibition of RIPK1 had a significant but modest beneficial effect; however, the inhibitors used in that study had suboptimal pharmacokinetic properties. In this work we evaluated both pharmacological and genetic inhibition of RIPK1 kinase activity. Lifespan in both Npc1−/−mice treated with GSK’547, a RIPK1 inhibitor with better pharmacokinetic properties, and Npc1−/− :Ripk1kd/kd double mutant mice was significantly increased. In both cases the increase in lifespan was modest, suggesting that the therapeutic potential of RIPK1 inhibition, as a monotherapy, is limited. We thus investigated the potential of combining RIPK1 inhibition with 2-hydroxypropyl-β-cyclodextrin (HPβCD) therapy HPβCD has been shown to slow neurological disease progression in NPC1 mice, cats and patients. HPpβCD appeared to have an additive positive effect on the pathology and survival of Npc1−/−:Ripk1kd/kd mice. RIPK1 and RIPK3 are both critical components of the necrosome, thus we were surprised to observe no increase survival in Npc1−/−;Ripk3−/− mice compared to Npc1−/− mice. These data suggest that although necroptosis is occurring in NPC1, the observed effects of RIPK1 inhibition may be related to its RIPK3-independent role in neuroinflammation and cytokine production.

show abstract

“…PC-12 is a rat pheochromocytoma cell line of neuroendocrine origin derived from the adrenal glands. This cell line has been used as a model system to evaluate the cytotoxic and neurotoxic effects of various substances (14)(15)(16). We used PC-12 cells to elucidate the mechanism underlying the anticancer effects of UA.…”

mentioning

confidence: 99%

Ursolic Acid Causes Cell Death in PC-12 Cells by Inducing Apoptosis and Impairing Autophagy

Jung

Seo

Kim

et al. 2018

View full text Add to dashboard Cite

Ursolic acid (UA) is a natural pentacyclic triterpene that has various biological activities, including anticancer and anti-inflammatory effects. This study investigated the ability of UA to cause cell death in pheochromocytoma (PC-12) cells. UA was cytotoxic to PC-12 cells (half-maximum inhibitory concentration=53.2 μM) and significantly reduced the clonogenic ability of PC-12 cells. It also triggered apoptosis by reducing the level of B-cell lymphoma 2 (BCL2), activating caspase-3, and inducing cleavage of poly (ADP-ribosyl) polymerase. To investigate the effects of UA treatment on the induction and progression of autophagy, the levels of p62 and the conversion of the microtubule-associated protein light chain 3 (LC3)-I to LC3-II, which are important markers of autophagic flux, were monitored. UA treatment induced the accumulation of p62 and increased the LC3-II/LC3-I ratio. These results demonstrate that UA treatment induced autophagy, but the downstream signaling pathway was blocked. In summary, this study shows that UA kills PC-12 cells by inducing apoptosis and impairing autophagy progression.

show abstract

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

Cited by 12 publications

References 59 publications

Hypoxia Modulates Effects of Fatty Acids on NES2Y Human Pancreatic β-cells

Hypoxia Modulates Effects of Fatty Acids on NES2Y Human Pancreatic β-cells

Necroptosis inhibition as a therapy for Niemann-Pick disease, type C1: Inhibition of RIP kinases and combination therapy with 2-hydroxypropyl-β-cyclodextrin

Ursolic Acid Causes Cell Death in PC-12 Cells by Inducing Apoptosis and Impairing Autophagy

Contact Info

Product

Resources

About