Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2^high Breast Cancer

Abstract

We propose that the ETC is a suitable therapeutic target in Her2 disease. Antioxid. Redox Signal. 26, 84-103.

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

“…It is evident that, despite the well-known Warburg effect, tumors have active mitochondrial bioenergetic metabolism (Marin-Valencia et al, 2012;Hensley et al, 2016). Disruption of the ETC shows promise in cancer therapy (Rohlena et al, 2011;Zhang et al, 2014;Rohlenova et al, 2017). Cells with deleterious mtDNA mutations fail to form tumors (Park et al, 2009), and genetic ablation of OXPHOS restrains tumorigenesis (Weinberg et al, 2010).…”

“…While we propose that targeting DHODH may present a novel, broad-spectrum anti-cancer strategy, we note that there are mitochondrial inhibitors that are under clinical trial, such as inhibitors of complex I (Molina et al, 2018;Rohlenova et al, 2017) or a-ketoglutarate dehydrogenase (Alistar et al, 2017), which effectively suppress tumor growth without DHODH inhibition. In addition, it can be expected that DHODH inhibition will not be effective in all types of tumors, and that combined targeting involving DHODH and complex I may provide a broader and more effective anti-cancer strategy by simultaneously interfering with two crucial steps of pyrimidine biosynthesis.…”

“…As relevant, the high-resolution Oxygraph-2k respirometer (Oroboros) and the Seahorse XF96 Extracellular Flux Analyzer (Agilent Technologies) were used. Routine, CI-and CII-dependent respiration was assessed as published (Boukalova et al, 2016;Rohlenova et al, 2017). DHODH-dependent respiration was carried out as follows.…”

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells

“…From translational angle, recent studies on horizontal mitochondrial transfer indicate two tantalising, novel approaches to cancer therapy: targeting mitochondrial respiration and blocking transfer of mitochondria from stromal cells to cancer cells. While we have started exploring the first approach (Dong et al, 2011; Boukalova et al, 2016; Kluckova et al, 2015; Rohlenova et al, 2017), the other approach remains untested, with recent papers (Osswald et al, 2015; Moschoi et al, 2016) pointing to its plausibility. Finally, to the best of our knowledge, this paper is the first report to show lasting functional consequences of a well-documented mitochondrial transfer event.…”

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

“…Mitochondrial respiration was assessed as described previously (53). Briefly, SUM159PT or MDA-MB-231 were grown to 50-70% confluence, treated with Mzb (100 nM) for 9 h and 24 h, respectively.…”