title: Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.
abstract: 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 outcomes. 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 was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed 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.
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina e Chirurgia "A. Gemelli", Università Cattolica del Sacro Cuore , Largo F. Vito 1, 00168 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Trapani
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina e Chirurgia "A. Gemelli", Università Cattolica del Sacro Cuore , Largo F. Vito 1, 00168 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Luongo
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina e Chirurgia "A. Gemelli", Università Cattolica del Sacro Cuore , Largo F. Vito 1, 00168 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Arduini
authors.affiliation: Istituto di Patologia Generale, Facoltà di Medicina e Chirurgia "A. Gemelli", Università Cattolica del Sacro Cuore , Largo F. Vito 1, 00168 Rome, Italy.
authors.forename: Federica I
authors.initials: FI
authors.lastname: Wolf
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism*; D061986:MCF-7 Cells; D008274:Magnesium / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D050053:TRPM Cation Channels; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008274:Magnesium