Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer.
The metabolic network of cancer cells confers adaptive mechanisms against many chemotherapeutic agents, but also presents critical constraints that make the cells vulnerable to perturbation of the network due to drug therapy. To identify these fragilities, combination therapies based on targeting the nucleic acid synthesis metabolic network at multiple points were tested. Results showed that cancer cells overcome single hit strategies through different metabolic network adaptations, demonstrating the robustness of cancer cell metabolism. Analysis of these adaptations also identified the maintenance of pentose phosphate cycle oxidative and nonoxidative balance to be critical for cancer cell survival and vulnerable to chemotherapeutic intervention. The vulnerability of cancer cells to the imbalance on pentose phosphate cycle was demonstrated by phenotypic phase plane analysis.
Ramos-Montoya
Antonio
A
Department of Biochemistry and Molecular Biology, Faculty of Biology, CeRQT-Parc Cientific de Barcelona, University of Barcelona, Barcelona, Spain.
Lee
Wai-Nang P
WN
Bassilian
Sara
S
Lim
Shu
S
Trebukhina
Raisa V
RV
Kazhyna
Maria V
MV
Ciudad
Carlos J
CJ
Noé
Véronique
V
Centelles
Josep J
JJ
Cascante
Marta
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010119:Oxythiamine / Q000008:administration & dosage / Q000494:pharmacology; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D012267:Ribosemonophosphates / Q000037:antagonists & inhibitors / Q000378:metabolism
D006131:Growth Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D012267:Ribosemonophosphates; D010119:Oxythiamine; D003687:Dehydroepiandrosterone; C031626:ribose-5-phosphate; D008727:Methotrexate