The role of lysosomes in limiting drug toxicity in mice.
The distribution behavior of a drug within a cell is an important, yet often overlooked, variable in both activity and differential selectivity. In normal cells, drugs with weakly basic properties are known to be extensively compartmentalized in acidic organelles such as lysosomes via ion trapping. Several cancer cell lines have been shown to have defective acidification of endocytic organelles and therefore have a diminished capacity to sequester such lysosomotropic agents. In this study, we tested the hypothesis that the low lysosomal pH of normal cells plays an important role in protecting normal tissues from the toxic effects of lysosomotropic anticancer drugs. The influence of lysosomal pH status on the toxicity of inhibitors of the molecular chaperone Hsp90 that did or did not possess lysosomotropic properties was evaluated in mice. Toxicity of Hsp90 inhibitors was evaluated in normal mice and in mice treated with chloroquine to elevate lysosomal pH by assessing morbidity and utilizing biochemical assays to diagnose hepatic and renal toxicity. Toxicity of the lysosomotropic inhibitor 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) was significantly enhanced in mice with elevated lysosomal pH relative to mice with normal lysosomal pH. In contrast, elevation of lysosomal pH had no significant impact on toxicity of the nonlysosomotropic inhibitor geldanamycin. These results support the notion that the low lysosomal pH of normal cells plays an important role in protecting these cells from the toxic effects of anticancer agents with lysosomotropic properties and has implications for the design/selection of anticancer drugs with improved safety and differential selectivity.
Ndolo
Rosemary A
RA
Department of Pharmaceutical Chemistry, University of Kansas School of Pharmacy, Lawrence, Kansas, USA.
Forrest
M Laird
ML
Krise
Jeffrey P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001119:Arginase / Q000097:blood; D016227:Benzoquinones / Q000493:pharmacokinetics / Q000633:toxicity*; D002738:Chloroquine / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D007677:Kidney Function Tests; D047029:Lactams, Macrocyclic / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D002738:Chloroquine; D003404:Creatinine; C544448:Arg1 protein, mouse; D001119:Arginase; C001277:geldanamycin