Differential effects of aminosubstituted analogs of hydroxy bisphosphonates on the growth of Dictyostelium discoideum.
Replacing the hydroxyl group in the bone-binding site of three clinically useful bisphosphonates (etidronate, pamidronate, and olpadronate) by an amino group resulted in great differences in their antiresorptive potencies in vitro. In the present study, this is also shown in vivo in mice treated with the six bisphosphonates at doses of up to 16 microM/kg/day for 12 days. Because binding to bone mineral is nearly the same for all tested bisphosphonates, these findings suggest that the aminosubstitution affects the cellular action of the bisphosphonates. This was tested in the cellular slime mould Dictyostelium discoideum in which cellular effects of bisphosphonates can be examined independently of binding to bone mineral. Etidronate and its aminosubstituted analog were equipotent in inhibiting amebal growth, while pamidronate was somewhat more potent than its analog. Whereas olpadronate was a potent inhibitor of axenic growth of Dictyostelium amebae, the aminosubstitution reduced its potency drastically (IC50 12 microM and 700 microM, respectively). The similarities between the inhibitory effects of the bisphosphonates tested on bone resorption in vitro and in vivo and on the growth of Dictyostelium amebae confirm that the differences in antiresorptive potencies found reflect differences in cellular effects and suggest that bisphosphonates may bind to more than one intracellular target.
Brown
R J
RJ
Department of Molecular Biology and Biotechnology, University of Sheffield, United Kingdom.
van Beek
E
E
Watts
D J
DJ
Löwik
C W
CW
Papapoulos
S E
SE
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000517:prevention & control*; D004023:Dictyostelium / Q000187:drug effects* / Q000254:growth & development; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000494:pharmacology; D005260:Female; D006614:Hindlimb; D051379:Mice; D000077268:Pamidronate; D013329:Structure-Activity Relationship
D000588:Amines; D004164:Diphosphonates; C055774:olpadronic acid; D012968:Etidronic Acid; D000077268:Pamidronate