Enhancement of doxorubicin content by the antitumor drug lonidamine in resistant Ehrlich ascites tumor cells through modulation of energy metabolism

The effect of the antitumor drug lonidamine (LND) on respiration, aerobic glycolysis, adenylate pool, doxorubicin (DOX) uptake, and efflux in DOX-resistant and DOX-sensitive Ehrlich tumor cells was investigated. The results may be summarized as follows: 1) In both types of cells, LND inhibited both respiration and glycolysis in a dose-dependent manner and lowered the ATP concentration. The effect was more marked in cells incubated in glucose-free medium; 2) LND raised, to a remarkable extent, the intracellular content of DOX in resistant and sensitive cells respiring on endogenous substrates because of reduced ATP availability, whereas in glucose-supplemented medium, where both respiration and glycolysis contributed to ATP synthesis, the increase was lower; and 3) when LND was added to DOX-loaded cells, it failed to significantly inhibit DOX efflux because of time-dependent phenomena. These findings indicated that LND, a drug currently employed in tumor therapy, might also be useful in reducing or overcoming multidrug resistance (MDR) of those cells with a reduced ability to accumulate and retain antitumor drugs.