Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity

S. Suri, J. Monkkonen, M. Blank, R. J. Phipps, Michael John Rogers

Research output: Contribution to journalArticle

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Abstract

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 mu mol/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. (C) 2001 by Elsevier Science Inc. All rights reserved.

Original languageEnglish
Pages (from-to)336-343
Number of pages7
JournalBone
Volume29
DOIs
Publication statusPublished - 2001

Keywords

  • bisphosphonate
  • apoptosis
  • Caco-2
  • mevalonate
  • prenylation
  • epithelium
  • RESORPTIVE BONE-DISEASE
  • IN-VITRO
  • OSTEOCLAST FORMATION
  • PHARMACOLOGICAL PROPERTIES
  • THERAPEUTIC EFFICACY
  • GASTRIC-ULCERS
  • ALENDRONATE
  • PAMIDRONATE
  • CLODRONATE
  • ACTIVATION

Cite this

Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. / Suri, S.; Monkkonen, J.; Blank, M.; Phipps, R. J.; Rogers, Michael John.

In: Bone, Vol. 29, 2001, p. 336-343.

Research output: Contribution to journalArticle

Suri, S. ; Monkkonen, J. ; Blank, M. ; Phipps, R. J. ; Rogers, Michael John. / Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. In: Bone. 2001 ; Vol. 29. pp. 336-343.
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abstract = "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 mu mol/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. (C) 2001 by Elsevier Science Inc. All rights reserved.",
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T1 - Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity

AU - Suri, S.

AU - Monkkonen, J.

AU - Blank, M.

AU - Phipps, R. J.

AU - Rogers, Michael John

PY - 2001

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N2 - 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 mu mol/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. (C) 2001 by Elsevier Science Inc. All rights reserved.

AB - 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 mu mol/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. (C) 2001 by Elsevier Science Inc. All rights reserved.

KW - bisphosphonate

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KW - Caco-2

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KW - IN-VITRO

KW - OSTEOCLAST FORMATION

KW - PHARMACOLOGICAL PROPERTIES

KW - THERAPEUTIC EFFICACY

KW - GASTRIC-ULCERS

KW - ALENDRONATE

KW - PAMIDRONATE

KW - CLODRONATE

KW - ACTIVATION

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DO - 10.1016/S8756-3282(01)00589-0

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VL - 29

SP - 336

EP - 343

JO - Bone

JF - Bone

SN - 8756-3282

ER -