Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity.
Bisphosphonates have become an important addition to the pharmacological armamentarium against postmenopausal osteoporosis. One of the major side effects of oral therapy with some nitrogen-containing bisphosphonates appears to be gastrointestinal (GI) intolerability, particularly esophageal irritation and ulceration. Because nitrogen-containing bisphosphonates can cause apoptosis in a variety of cell types in vitro, by inhibiting the mevalonate pathway, we hypothesized that the effect of these agents on the GI tract may be due to apoptosis or inhibition of growth of gut epithelial cells. A comparison between clodronate, etidronate, pamidronate, alendronate, and risedronate demonstrated that only the nitrogen-containing bisphosphonates were effective at inducing apoptosis or inhibiting proliferation of Caco-2 human epithelial cells in vitro, at concentrations of between 10 and 1000 micromol/L. The ability of nitrogen-containing bisphosphonates to cause apoptosis and inhibit Caco-2 cell proliferation was due to inhibition of the mevalonate pathway, because the addition of farnesol, oxidized low-density lipoprotein (LDL) cholesterol, or especially geranylgeraniol suppressed the effects. Furthermore, pamidronate, alendronate, and risedronate inhibited protein prenylation in Caco-2 cells, as determined by analysis of the processing of Rap1A, a prenylated small GTPase. These studies suggest that the effects of nitrogen-containing bisphosphonates observed in the GI tract may be due to inhibition of proliferation or apoptosis of gut epithelial cells, following loss of prenylated proteins and sterols.
Suri
S
S
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, UK.
Mönkkönen
J
J
Taskinen
M
M
Pesonen
J
J
Blank
M A
MA
Phipps
R J
RJ
Rogers
M J
MJ
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000633:toxicity*; D004224:Diterpenes / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008798:Mevalonic Acid / Q000378:metabolism*; D017672:Nitrogen Compounds / Q000633:toxicity*; D017368:Protein Prenylation; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D004164:Diphosphonates; D004224:Diterpenes; D017672:Nitrogen Compounds; C017338:geranylgeraniol; D020827:rap1 GTP-Binding Proteins; D008798:Mevalonic Acid