Modulation of doxorubicin resistance by the glucose 6-phosphate dehydrogenase activity

How anti-neoplastic agents induce multidrug resistance (MDR) in cancer cells and the role of glutathione (GSH) in the activation of pumps such as the multidrug resistance-associated proteins (MRPs) are still open questions. In this paper we illustrate that a doxorubicin-resistant human colon cancer cell line (HT29-DX), exhibiting decreased doxorubicin accumulation and increased intracellular GSH content and MRP1 and MRP2 expression in comparison to doxorubicin-sensitive HT29 cells, shows increased activity of the pentose phosphate pathway (PPP) and of glucose 6-phosphate dehydrogenase (G6PD). We observed the onset of MDR in HT29 cells overexpressing G6PD, accompanied by an increase of GSH; the G6PD inhibitors dehydroepiandrosterone (DHEA) and 6-aminonicotinamide (6-AN) 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 multidrug resistant cells to keep high the GSH content, 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 acquisi