title: Hypoxia-resistant profile implies vulnerability of cancer stem cells to physiological agents, which suggests new therapeutic targets.
abstract: We have previously shown that peculiar metabolic features of cell adaptation and survival in hypoxia imply growth restriction points that are typical of embryonic stem cells and disappear with differentiation. Here we provide evidence that such restrictions can be exploited as specific antiblastic targets by physiological factors such as pyruvate, tetrahydrofolate, and glutamine. These metabolites act as powerful cytotoxic agents on cancer stem cells (CSCs) when supplied at doses that perturb the biochemical network, sustaining the resumption of aerobic growth after the hypoxic dormant state. Experiments were performed in vivo and in vitro using CSCs obtained from various anaplastic tumors: human melanoma, leukemia, and rat hepatoma cells. Pretreatment of melanoma CSCs with pyruvate significantly reduces their self-renewal in vitro and tumorigenicity in vivo. The metabolic network underlying the cytotoxic effect of the physiological factors was thoroughly defined, principally using AH130 hepatoma, a tumor spontaneously reprogrammed to the embryonic stem stage. This network, based on a tight integration of aerobic glycolysis, cellular redox state, and folate metabolism, is centered on the cellular NADP/NADPH ratio that controls the redox pathway of folate utilization in purine synthesis. On the whole, this study indicates that pyruvate, FH 4, and glutamine display anticancer activity, because CSCs are committed to survive and maintain their stemness in hypoxia. When CSC need to differentiate and proliferate, they shift from anaerobic to aerobic status, and the few mitochondria available makes them susceptible to the injury of the above physiological factors. This vulnerability might be exploited for novel therapeutic treatments.
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cipolleschi
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marzi
authors.affiliation: Laboratory of Tumor Cell Biology; Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT); Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Santini
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Fredducci
authors.affiliation: Laboratory of Tumor Cell Biology; Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT); Florence, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Vinci
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Theodora
authors.initials: T
authors.lastname: Stivarou
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
authors.affiliation: Laboratory of Tumor Cell Biology; Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT); Florence, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stecca
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences; University of Florence; Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Olivotto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000187:drug effects; D002952:Citric Acid Cycle; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008545:Melanoma / Q000473:pathology; D053858:Metabolic Networks and Pathways; D008938:Mitosis; D009249:NADP / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013763:Tetrahydrofolates / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013763:Tetrahydrofolates; D005973:Glutamine; D009249:NADP; D019289:Pyruvic Acid
keywords: Krebs cycle substrates; cancer stem cells; cellular redox-state; folate metabolism; hypoxia