title: The complex metabolic network gearing the G1/S transition in leukemic stem cells: Hints to a rational use of antineoplastic agents.
abstract: We defined the stem cell profile of K562 line, demonstrating the expression of the Embryonic Transcription Factors Oct3/4, Sox2, Klf4 and Nanog. This profile was associated with a high vulnerability to the physiological oxidizable substrate pyruvate. remarkably, this substrate was shown to be innocuous, even at the highest doses, to normal differentiated cells. This vulnerability is based on a complex metabolic trim centered on the cellular redox state expressed by the NADP/NADPH ratio geared by the mitochondrial respiratory chain. Flow cytometry revealed that the inhibition of this chain by antimycin A produced cell accumulation in the S phase of cell cycle and apoptosis. This block negatively interferes with the aerobic synthesis of purines, without affecting the anaerobic synthesis of pyrimidines. This imbalance was reproduced by using two antifolate agents, LY309887 and raltitrexed (TDX), inhibitors of purine or pyrimidine synthesis, respectively. All this revealed the apparent paradox that low doses of TDX stimulated, instead of inhibiting, leukemia cell growth. This paradox might have significant impact on therapy with regard to the effects of TDX during the intervals of administration, when the drug concentrations become so low as to promote maintenance of dormant cancer cells in hypoxic tissue niches.
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.|Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Stivarou
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cipolleschi
authors.affiliation: DI.V.A.L. Toscana s.r.l., Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mannini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Olivotto
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marzi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005493:Folic Acid Antagonists / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D000090062:Kruppel-Like Factor 4; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011773:Pyruvates / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D011773:Pyruvates
keywords: LY309887 and raltitrexed; embryonic transcription factors; folate metabolism; hypoxia; redox state