The complex metabolic network gearing the G1/S transition in leukemic stem cells: Hints to a rational use of antineoplastic agents
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Theodora Stivarou1,4,*, Maria Grazia Cipolleschi1,*, Massimo D'Amico2, Antonella Mannini3, Enrico Mini3, Elisabetta Rovida1, Persio Dello Sbarba1, Massimo Olivotto1, Ilaria Marzi1
1Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy
2DI.V.A.L. Toscana s.r.l., Florence, Italy
3Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
4Hellenic Pasteur Institute, Athens, Greece
*These authors have contributed equally to this work
Ilaria Marzi, e-mail: [email protected]
Keywords: hypoxia, embryonic transcription factors, LY309887 and raltitrexed, folate metabolism, redox state
Received: March 20, 2015 Accepted: August 28, 2015 Published: September 11, 2015
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.
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