Cardiac glycosides modulate neuroblastoma stem cell survival by dysfunctional mitophagy

Marc Diederich Targeting Mitochondria 2019The Scientific Committee of WMS is honored to announce that Dr. Marc Diederich, of the College of Pharmacy, Seoul National University, Korea, will be joining us for our 10th Anniversary Edition of Targeting Mitochondria World Congress, which will be held in Berlin on October 28th-29th, 2019.

In his presentation entitled "Cardiac glycosides modulate neuroblastoma stem cell survival by dysfunctional mitophagy", Dr. Diederich will discuss the limiting factor to producing successful therapeutic outcomes in children with high-risk neuroblastoma, resistant to chemotherapeutic therapies. Therefore, a better characterisation of sensitive versus resistant neuroblastoma cell types is urgently required. Our previous research showed that the cardiac glycoside (CG) UNBS1450 (1,2) exerted its anti-cancer activity in neuroblastoma through an early induction of mitophagy in response to a mitochondrial stress response: whereas UNBS1450 rapidly promoted apoptosis in N-type (SH-SY5Y) cells, necroptosis was triggered in the more resistant S-type (SK-N-AS) cells at higher concentrations and later time points. In SH-SY5Y cells, reactive oxygen species generation triggered loss of Δψ and accumulation of mitochondria in phagophores/autophagosomes, suggesting impaired clearance of damaged mitochondria (3). Moreover, differential expression of p53, stem cell homeostasis, and pluripotency recently gained interest in neuroblastoma research. Here, we aimed at identifying critical determinants of the differential sensitivity towards UNBS1450 in neuroblastoma cells to improve prediction of the treatment response. First, we selected the most sensitive neuroblastoma cell subtype based on p53 and neuroblastoma CSC marker expression levels. Second, in the most sensitive subtype, we further aimed at assessing mitochondrial quality control mechanisms to identify mitochondrial biomarkers of UNBS1450 efficacy.     

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