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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 M, Heymann D - J. Cell. Mol. Med. (2008)

Bottom Line: Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype.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.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France.

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.

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FPPS siRNA increases the Zol-induced blockade of the cell cycle in S phases in osteosarcoma cell lines. Cell cycle distribution of osteosarcoma cell lines (FPPS siRNA versus control siRNA) treated or not treated with 10 μm Zol for 48 hrs were analyzed by propidium iodide staining and FACS analysis.
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fig04: FPPS siRNA increases the Zol-induced blockade of the cell cycle in S phases in osteosarcoma cell lines. Cell cycle distribution of osteosarcoma cell lines (FPPS siRNA versus control siRNA) treated or not treated with 10 μm Zol for 48 hrs were analyzed by propidium iodide staining and FACS analysis.

Mentions: We previously demonstrated that Zol induces osteosarcoma cell cycle arrest in S, G2/M phases in OSRGA sensitive cells [13]. To determine whether FPPS siRNA could modulate this sensitivity, the cell cycle of FPPS siRNA-transfected osteosarcoma cells was analyzed by flow cytometry. Figure 4 reveals that FPPS siRNA accentuates the Zol-induced effects observed on cell-cycle distribution, leading to a significant increase of cells blocked in S phase compared to the control siRNA. Indeed, the number of cells in S phase increased from 26% to 30% for OSRGA, from 20% to 26% for MG63, from 34% to 46% for SAOS2 and from 23% to 38% for OSRGAres cells in the presence of FPPS siRNA compared to the control siRNA after 48 hrs of treatment with 10 μm Zol (Fig. 4). Furthermore, these observations were concomitant with a significant reduction of the cell number in G0/G1 phase:35%versus 42% for OSRGA, 61%versus 69% for MG63, 36%versus 57% for SAOS2 and 41%versus 53% for OSRGAres.


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 M, Heymann D - J. Cell. Mol. Med. (2008)

FPPS siRNA increases the Zol-induced blockade of the cell cycle in S phases in osteosarcoma cell lines. Cell cycle distribution of osteosarcoma cell lines (FPPS siRNA versus control siRNA) treated or not treated with 10 μm Zol for 48 hrs were analyzed by propidium iodide staining and FACS analysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401135&req=5

fig04: FPPS siRNA increases the Zol-induced blockade of the cell cycle in S phases in osteosarcoma cell lines. Cell cycle distribution of osteosarcoma cell lines (FPPS siRNA versus control siRNA) treated or not treated with 10 μm Zol for 48 hrs were analyzed by propidium iodide staining and FACS analysis.
Mentions: We previously demonstrated that Zol induces osteosarcoma cell cycle arrest in S, G2/M phases in OSRGA sensitive cells [13]. To determine whether FPPS siRNA could modulate this sensitivity, the cell cycle of FPPS siRNA-transfected osteosarcoma cells was analyzed by flow cytometry. Figure 4 reveals that FPPS siRNA accentuates the Zol-induced effects observed on cell-cycle distribution, leading to a significant increase of cells blocked in S phase compared to the control siRNA. Indeed, the number of cells in S phase increased from 26% to 30% for OSRGA, from 20% to 26% for MG63, from 34% to 46% for SAOS2 and from 23% to 38% for OSRGAres cells in the presence of FPPS siRNA compared to the control siRNA after 48 hrs of treatment with 10 μm Zol (Fig. 4). Furthermore, these observations were concomitant with a significant reduction of the cell number in G0/G1 phase:35%versus 42% for OSRGA, 61%versus 69% for MG63, 36%versus 57% for SAOS2 and 41%versus 53% for OSRGAres.

Bottom Line: Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype.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.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France.

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.

Show MeSH
Related in: MedlinePlus