Magnesium modulates doxorubicin activity through drug lysosomal sequestration and trafficking

Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcome. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells, and found that high magnesium availability correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations, and in acutely magnesium-supplemented cells. Such decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation, in the face of a similar drug uptake rate. We show that high magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.