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// Silvia Vidali 1 , Sepideh Aminzadeh-Gohari 1 , Rene Gunther Feichtinger 1 , Renaud Vatrinet 2 , Andreas Koller 1 , Felix Locker 1 , Tricia Rutherford 3 , Maura O’Donnell 3 , Andrea Stoger-Kleiber 3 , Bridget Lambert 3 , Thomas Klaus Felder 4 , Wolfgang Sperl 5 and Barbara Kofler 1 1 Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria 2 Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy 3 Clinical Nutrition, Vitaflo International Ltd, Liverpool, UK 4 Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria 5 Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria Correspondence to: Barbara Kofler, email: b.kofler@salk.at Keywords: renal cell carcinoma, mitochondria, ketogenic diet, metabolism, Warburg effect Received: March 10, 2017 Accepted: June 27, 2017 Published: July 17, 2017 ABSTRACT The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer’s syndrome, because they potentially worsen the associated hepatic dysfunction.

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control.

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials., Lack of respiratory complex I is a hallmark of oncocytomas. Here the authors show that inactivation of this complex via knockout of the NDUFS3 subunit or using metformin, converts tumors from an aggressive phenotype into low-proliferative oncocytomas, which can be further inhibited by targeting pro-tumorigenic macrophages.

Deregulated metabolism is a well-established hallmark of cancer. At the hub of various metabolic pathways deeply integrated within mitochondrial functions, the α-ketoglutarate dehydrogenase complex represents a major modulator of electron transport chain activity and tricarboxylic acid cycle (TCA) flux, and is a pivotal enzyme in the metabolic reprogramming following a cancer cell’s change in bioenergetic requirements. By contributing to the control of α-ketoglutarate levels, dynamics, and oxidation state, the α-ketoglutarate dehydrogenase is also essential in modulating the epigenetic landscape of cancer cells. In this review, we will discuss the manifold roles that this TCA enzyme and its substrate play in cancer.

Introduction Dans le cadre d’un essai clinique vaccinal international de phase II en communaute, les donnees biologiques constituent un element important de l’evaluation a court terme de la tolerance. Un systeme de gestion en temps reel des donnees biologiques a ete mis en place afin de prendre en compte les specificites des sites investigateurs et de permettre une centralisation des donnees. Methodes PREVAC est un essai clinique de phase II, multicentrique, randomise, en double insu, visant a evaluer la tolerance et l’immunogenicite de trois strategies vaccinales anti-Ebola contre placebo. Entre mars 2017 et novembre 2018, 4720 participants ont ete inclus sur six sites en Guinee, au Liberia, au Mali et en Sierra Leone. Afin d’evaluer la tolerance a court terme du vaccin, des prelevements sanguins sont effectues a l’inclusion et en post-vaccination. Les analyses sont realisees le jour meme au sein des laboratoires des sites. Les resultats bruts sont envoyes au centre de traitement des donnees de la plate-forme Euclid/F-CRIN qui gere la base de donnees centralisee de l’essai. Les controles de coherence, l’ajout des valeurs de reference par pays et le calcul des grades de severite (DAIDS, v2.0, 2014) ont ete effectues avec le logiciel SAS 9.4. Les resultats sont integres dans la base de donnees centralisee et retranscrits dans des rapports edites en francais et en anglais mis a disposition des sites (medecins et participants) dans les 24 h ouvrees suivant les prelevements. Deux statisticiens et deux data managers sont impliques pour assurer la continuite de l’actualisation de la base de donnees. Resultats Entre mars 2017 et novembre 2018, les resultats de 8640 prelevements effectues chez 4713 participants ont ete centralises. Les resultats biologiques ont ete rendus disponibles dans les 24 h ouvrees dans 86 % des cas. Pour les resultats traites dans un delai de plus de 24 h, le delai median de rendu etait de 2 jours. Des extractions des grades de severite et des aggravations biologiques ont ete envoyees toutes les semaines aux equipes de monitorage. Conclusion Cette approche, fondee sur l’harmonisation du recueil et la centralisation des valeurs biologiques en temps reel, a permis un suivi de la tolerance biologique des vaccins administres en traitant les resultats sur des delais tres courts permettant l’edition de rapports de resultats personnalises et accessibles tout en prenant en compte les specificites (langage, valeurs normales) des populations concernees ( Fig. 1 ).

In the last 10 years, studies of energetic metabolism in different tumors clearly indicate that the definition of Warburg effect, i.e. the glycolytic shift cells undergo upon transformation, ought to be revisited considering the metabolic plasticity of cancer cells. In fact, recent findings show that the shift from glycolysis to re-established oxidative metabolism is required for certain steps of tumor progression, suggesting that mitochondrial function and, in particular, respiratory complex I are crucial for metabolic and hypoxic adaptation. Based on these evidences, complex I can be considered a lethality target for potential anticancer strategies. In conclusion, in this mini review we summarize and discuss why it is not paradoxical to develop pharmacological and genome editing approaches to target complex I as novel adjuvant therapies for cancer treatment. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

Articular chondrocytes are responsible for the maintenance of healthy articulations; indeed, dysregulation of their functions, including the production of matrix proteins and matrix-remodeling proteases, may result in fraying of the tissue and development of osteoarthritis (OA). To explore transcriptional mechanisms that contribute to the regulation of chondrocyte homeostasis and may be implicated in OA development, we compared the gene expression profile of a set of zinc finger proteins potentially linked to the control of chondrocyte differentiation and/or functions (ZNF423, ZNF470, ZNF521, and ZNF780B) in chondrocytes from patients affected by OA and from subjects not affected by OA. This analysis highlighted a significantly lower expression of the transcript encoding ZNF423 in chondrocytes from OA, particularly in elderly patients. Interestingly, this decrease was mirrored by the similarly reduced expression of PPARγ, a known target of ZNF423 with anti-inflammatory and chondroprotective properties. The ZNF521 mRNA instead was abundant in all primary chondrocytes studied; the RNAi-mediated silencing of this gene significantly altered the COL2A/COL1 expression ratio, associated with the maintenance of the differentiated phenotype, in chondrocytes cultivated in alginate beads. These results suggest a role for ZNF423 and ZNF521 in the regulation of chondrocyte homeostasis and warrant further investigations to elucidate their mechanism of action.