Limits...
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.

Show MeSH

Related in: MedlinePlus

The molecular mechanism involved in the reduced-Zol sensitivity is not associated with a multidrug resistance (MDR) phenotype and is restricted to the nitrogen-containing bisphosphonates. OSRGA and OSRGAres sensitivity to conventional anti-cancer agents mafosfamide, methotrexate, doxorubicin and sensitivity to Zol in the presence or absence of a P-gp pump inhibitor (5 μm verapamil) was analyzed by the XTT assay. Similar experiments were performed in the presence of clodronate and pamidronate. Graphs represent the mean values of three independent experiments performed in triplicate. Error bars represent the standard deviation. ***P < 0.001. Statistical evaluation of the data was performed using the ANOVA test.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4401135&req=5

fig02: The molecular mechanism involved in the reduced-Zol sensitivity is not associated with a multidrug resistance (MDR) phenotype and is restricted to the nitrogen-containing bisphosphonates. OSRGA and OSRGAres sensitivity to conventional anti-cancer agents mafosfamide, methotrexate, doxorubicin and sensitivity to Zol in the presence or absence of a P-gp pump inhibitor (5 μm verapamil) was analyzed by the XTT assay. Similar experiments were performed in the presence of clodronate and pamidronate. Graphs represent the mean values of three independent experiments performed in triplicate. Error bars represent the standard deviation. ***P < 0.001. Statistical evaluation of the data was performed using the ANOVA test.

Mentions: The potential role of the MDR phenotype in the Zol resistance phenomenon was assessed by XTT assays. The MDR phenotype is conventionally defined as the resistance of cells to conventional chemotherapeutic agents such as mafosfamide, methotrexate and doxorubicin [20, 21]. The XTT assays revealed that OSRGAres cells were still always sensitive to increasing doses of mafosfamide, methotrexate and doxorubicin (Fig. 2). Furthermore, 5 μm verapamil, a P-gp pump inhibitor [22] was not able to abolish the Zol resistance (Fig. 2). Overall, these data demonstrate that the Zol resistance was not associated with MDR phenotype. In addition, similar experiments performed in the presence of clodronate, a non-nitrogen containing-BP [4], revealed that OSRGAres are as sensitive to clo-dronate as they are to lower concentrations of Zol (Fig. 2). When, osteosarcoma cells were treated with another nitrogen-containing BP, pamidronate that also targets FPPS, it significantly reduced Zol-sensitive OSRGA proliferation in contrast to OSRGAres cells, which are also resistant to pamidronate (Fig. 2). Similar results have been obtained with the osteosarcoma cell lines MG63 and SAOS2 (data not shown). These experiments demonstrated that the Zol-resistance phenomenon in osteosarcoma cells appears to be MDR-independent and is apparently restricted to nitrogen-containing BPs.


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)

The molecular mechanism involved in the reduced-Zol sensitivity is not associated with a multidrug resistance (MDR) phenotype and is restricted to the nitrogen-containing bisphosphonates. OSRGA and OSRGAres sensitivity to conventional anti-cancer agents mafosfamide, methotrexate, doxorubicin and sensitivity to Zol in the presence or absence of a P-gp pump inhibitor (5 μm verapamil) was analyzed by the XTT assay. Similar experiments were performed in the presence of clodronate and pamidronate. Graphs represent the mean values of three independent experiments performed in triplicate. Error bars represent the standard deviation. ***P < 0.001. Statistical evaluation of the data was performed using the ANOVA test.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: The molecular mechanism involved in the reduced-Zol sensitivity is not associated with a multidrug resistance (MDR) phenotype and is restricted to the nitrogen-containing bisphosphonates. OSRGA and OSRGAres sensitivity to conventional anti-cancer agents mafosfamide, methotrexate, doxorubicin and sensitivity to Zol in the presence or absence of a P-gp pump inhibitor (5 μm verapamil) was analyzed by the XTT assay. Similar experiments were performed in the presence of clodronate and pamidronate. Graphs represent the mean values of three independent experiments performed in triplicate. Error bars represent the standard deviation. ***P < 0.001. Statistical evaluation of the data was performed using the ANOVA test.
Mentions: The potential role of the MDR phenotype in the Zol resistance phenomenon was assessed by XTT assays. The MDR phenotype is conventionally defined as the resistance of cells to conventional chemotherapeutic agents such as mafosfamide, methotrexate and doxorubicin [20, 21]. The XTT assays revealed that OSRGAres cells were still always sensitive to increasing doses of mafosfamide, methotrexate and doxorubicin (Fig. 2). Furthermore, 5 μm verapamil, a P-gp pump inhibitor [22] was not able to abolish the Zol resistance (Fig. 2). Overall, these data demonstrate that the Zol resistance was not associated with MDR phenotype. In addition, similar experiments performed in the presence of clodronate, a non-nitrogen containing-BP [4], revealed that OSRGAres are as sensitive to clo-dronate as they are to lower concentrations of Zol (Fig. 2). When, osteosarcoma cells were treated with another nitrogen-containing BP, pamidronate that also targets FPPS, it significantly reduced Zol-sensitive OSRGA proliferation in contrast to OSRGAres cells, which are also resistant to pamidronate (Fig. 2). Similar results have been obtained with the osteosarcoma cell lines MG63 and SAOS2 (data not shown). These experiments demonstrated that the Zol-resistance phenomenon in osteosarcoma cells appears to be MDR-independent and is apparently restricted to nitrogen-containing BPs.

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