TY - JOUR
T1 - Magnesium modulates doxorubicin activity through drug lysosomal sequestration and trafficking
AU - Trapani, Valentina
AU - Luongo, Francesca
AU - Arduini, Daniela
AU - Wolf Minotti, Federica
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - breast cancer, chemotherapy, cytoskeleton, cytotoxicity, TRPM7
KW - breast cancer, chemotherapy, cytoskeleton, cytotoxicity, TRPM7
UR - http://hdl.handle.net/10807/75474
U2 - 10.1021/acs.chemrestox.5b00478
DO - 10.1021/acs.chemrestox.5b00478
M3 - Article
SN - 0893-228X
SP - 317
EP - 322
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
ER -