Proteomics and metabolomics in cancer drug development 5 Expert Rev. Proteomics 10(5), 000–000 (2013) Angelo D’Alessandro and Lello Zolla* Department of Ecological and Biological Sciences, University of Tuscia, Largo dell’Universita `, snc, 01100 Viterbo, Italy *Author for correspondence: Tel.: +39 0761 357 100 Fax: +39 0761 357 630 zolla@unitus.it In this review article, the main recent advancements in the field of proteomics and metabolomics and their application in cancer research are described. In the second part of 10 the review the main metabolic alterations observed in cancer cells are thoroughly dissected, especially those involving anabolic pathways and NADPH-generating pathways, which indirectly affect anabolic reactions, other than the maintenance of the redox poise. Alterations to mitochondrial pathways and thereby deriving oncometabolites are also detailed. The third section of the review is a discussion of how and to what extent (mutations to) 15 tumor suppressors and oncogenes end up influencing cancer cell metabolism and cell fate, either promoting survival and proliferation or autophagy and apoptosis. In the last section of the review, an overview is provided of therapeutic strategies that make use of metabolic reprogramming approaches. KEYWORDS: cancer • drug development • mass spectrometry • metabolism • proteomics Metabolomics, the new/old hallmark of 25 cancer Human tumor pathogenesis is characterized by the progressive accumulation of changes to nor- mal cells, changes that make cells evolve to a neoplastic state through the gradual acquisition 30 of a series of hallmark capabilities. This multi- step process utterly enables normal cells to become tumorigenic and, ultimately malig- nant [1]. While metabolic reprogramming has only recently been included in the list of the so- 35 called ‘hallmarks of cancer’ [1], echoes from the last (at least) 60 years of research already sug- gested a crucial correlation between chronic and uncontrolled cell proliferation and deregulated metabolism [2]. The ‘Warburg effect’, named 40 after Otto Warburg, the first researcher to docu- ment an exception to the Pasteur effect (inhibi- tion of glycolysis in presence of oxygen) in highly proliferating cancer cells, is based upon the appreciation of an increased glycolytic rate, 45 at the expenses of mitochondrial metabolism (preferentially exploited by normal differentiated cells for energy production purposes), even in the presence of oxygen [2]. This phenomenon, often referred to as ‘aerobic glycolysis’, was at 50 first deemed to be counterintuitive, since rapidly proliferating cells are supposed to have higher energy requirements, while a strictly glycolytic metabolism is less efficient than one relying upon mitochondrial oxidative phosphorylation in terms of ATP production (~18-fold lower efficiency) [3]. However, since generalization of a Warburg-like metabolism seems to be also appli- cable to many rapidly dividing embryonic tis- sues, a tentative explanatory and evidence-based theory posits that aerobic glycolysis might have evolved to meet the elevated anabolic demand (for biosynthetic purposes) and favor the uptake and incorporation of nutrients into biomass by rapidly dividing cells [3]. Conversely, over generalizations should be avoided as well, since tumor cells do not always display a Warburg-like metabolism. Indeed, some tumors are characterized by two subpopulations of cancer cells, one consisting of glucose-dependent cells that secrete lactate (Warburg-wise), while a second subpopulation almost symbiotically relies upon the secreted lactate to sustain their energy production via the tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) [1]. During the last decade, molecular evidences have underpinned a role for genetic reprog- ramming in the metabolic regulation observed in cancer cells, a phenomenon that is often accompanied by the preferential expression of cancer-specific isoforms of certain metabolic enzymes, or rather by peculiar and recurrent cancer-associated mutations, especially in genes coding for TCA cycle enzymes [4]. In the light Review www.expert-reviews.com 10.1586/14789450.2013.840440 Ó 2013 Informa UK Ltd ISSN 1478-9450 1