Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells

B Ory, G Moriceau, V Trichet, F Blanchard, M Berreur, F Rédini, Mike Rogers, D Heymann

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.
Original languageEnglish
Pages (from-to)928-941
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume12
Issue number3
Early online date21 May 2008
DOIs
Publication statusPublished - 1 Jun 2008

Fingerprint

zoledronic acid
Geranyltranstransferase
Osteosarcoma
pamidronate
Drug Resistance

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Diphosphonates
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Geranyltranstransferase
  • Humans
  • Imidazoles
  • Male
  • Middle Aged
  • Osteosarcoma
  • RNA, Small Interfering
  • Time Factors
  • Transfection

Cite this

Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells. / Ory, B; Moriceau, G; Trichet, V; Blanchard, F; Berreur, M; Rédini, F; Rogers, Mike; Heymann, D.

In: Journal of Cellular and Molecular Medicine, Vol. 12, No. 3, 01.06.2008, p. 928-941.

Research output: Contribution to journalArticle

Ory, B, Moriceau, G, Trichet, V, Blanchard, F, Berreur, M, Rédini, F, Rogers, M & Heymann, D 2008, 'Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells', Journal of Cellular and Molecular Medicine, vol. 12, no. 3, pp. 928-941. https://doi.org/10.1111/j.1582-4934.2008.00141.x
Ory, B ; Moriceau, G ; Trichet, V ; Blanchard, F ; Berreur, M ; Rédini, F ; Rogers, Mike ; Heymann, D. / Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells. In: Journal of Cellular and Molecular Medicine. 2008 ; Vol. 12, No. 3. pp. 928-941.
@article{c36a930bc97e40ba8b63af73d7db3904,
title = "Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells",
abstract = "We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Diphosphonates, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Female, Geranyltranstransferase, Humans, Imidazoles, Male, Middle Aged, Osteosarcoma, RNA, Small Interfering, Time Factors, Transfection",
author = "B Ory and G Moriceau and V Trichet and F Blanchard and M Berreur and F R{\'e}dini and Mike Rogers and D Heymann",
year = "2008",
month = "6",
day = "1",
doi = "10.1111/j.1582-4934.2008.00141.x",
language = "English",
volume = "12",
pages = "928--941",
journal = "Journal of Cellular and Molecular Medicine",
issn = "1582-1838",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells

AU - Ory, B

AU - Moriceau, G

AU - Trichet, V

AU - Blanchard, F

AU - Berreur, M

AU - Rédini, F

AU - Rogers, Mike

AU - Heymann, D

PY - 2008/6/1

Y1 - 2008/6/1

N2 - We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.

AB - We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Survival

KW - Diphosphonates

KW - Dose-Response Relationship, Drug

KW - Drug Resistance, Neoplasm

KW - Female

KW - Geranyltranstransferase

KW - Humans

KW - Imidazoles

KW - Male

KW - Middle Aged

KW - Osteosarcoma

KW - RNA, Small Interfering

KW - Time Factors

KW - Transfection

U2 - 10.1111/j.1582-4934.2008.00141.x

DO - 10.1111/j.1582-4934.2008.00141.x

M3 - Article

C2 - 18494934

VL - 12

SP - 928

EP - 941

JO - Journal of Cellular and Molecular Medicine

JF - Journal of Cellular and Molecular Medicine

SN - 1582-1838

IS - 3

ER -