title: Modulation of doxorubicin resistance by the glucose-6-phosphate dehydrogenase activity.
abstract: How anti-neoplastic agents induce MDR (multidrug resistance) in cancer cells and the role of GSH (glutathione) in the activation of pumps such as the MRPs (MDR-associated proteins) are still open questions. In the present paper we illustrate that a doxorubicin-resistant human colon cancer cell line (HT29-DX), exhibiting decreased doxorubicin accumulation, increased intracellular GSH content, and increased MRP1 and MRP2 expression in comparison with doxorubicin-sensitive HT29 cells, shows increased activity of the PPP (pentose phosphate pathway) and of G6PD (glucose-6-phosphate dehydrogenase). We observed the onset of MDR in HT29 cells overexpressing G6PD which was accompanied by an increase in GSH. The G6PD inhibitors DHEA (dehydroepiandrosterone) and 6-AN (6-aminonicotinamide) reversed the increase of G6PD and GSH and inhibited MDR both in HT29-DX cells and in HT29 cells overexpressing G6PD. In our opinion, these results suggest that the activation of the PPP and an increased activity of G6PD are necessary to some MDR cells to keep the GSH content high, which is in turn necessary to extrude anticancer drugs out of the cell. We think that our data provide a new further mechanism for GSH increase and its effects on MDR acquisition.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, Via Santena 5/bis, 10126 Torino, Italy. manuela.polimeni@unito.it
authors.forename: Manuela
authors.initials: M
authors.lastname: Polimeni
authors.forename: Claudia
authors.initials: C
authors.lastname: Voena
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Pescarmona
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005954:Glucosephosphate Dehydrogenase