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Ras Isoprenylation and pAkt Inhibition by Zoledronic Acid and Fluvastatin Enhances Paclitaxel Activity in T24 Bladder Cancer Cells.

Li S, De Souza P - Cancers (Basel) (2011)

Bottom Line: Western blots were used to assess effects on signal transduction pathways.Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment.Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition.

View Article: PubMed Central - PubMed

Affiliation: Cancer Pharmacology and Therapeutics Laboratory, St George Hospital, Kogarah, NSW, Australia. p.desouza@unsw.edu.au.

ABSTRACT

Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel.

Methods: Increasing doses of fluvastatin, zoledronic acid, and paclitaxel were investigated as single agents and in combination, and synergistic interactions were evaluated by the Chou-Talalay method. Western blots were used to assess effects on signal transduction pathways.

Results: Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment. Geranylgeranyl pyrophosphate and farnesyl pyrophosphate was able to block, in part, this inhibitory activity. The combinations of zoledronic acid and paclitaxel, zoledronic acid and fluvastatin, and fluvastatin and paclitaxel were all synergistic. Both fluvastatin and zoledronic acid inhibited Ras and Rap prenylation, and the phosphorylation of ERK1/2 and AKT. The degree of inhibition of phosphorylation of these key signaling transduction pathways appears to closely correlate with their synergistic interactions.

Conclusions: Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition.

No MeSH data available.


Related in: MedlinePlus

In vitro cytotoxicity of Fluvastatin and Zoledronic acid. T24 cells were exposed to a range of concentrations of fluvastatin (0.1 to 50 μM) and zoledronic acid (0.1 to 125 μM) for 24 to 72 hours as indicated, control cells treated identically except without adding drugs, the percentage of alive cells were detected by SRB method. The cytotocxicity of both drugs appeared dose and time dependant, T24 cells are slightly more sensitive to fluvastatin than to zoledronic acid, with an IC50 of 2.67 ± 0.61 μM for fluvastatin and 5.35 ± 1.35 μM for zoledronic acid at 72 hours treatment. Data represent the mean ± SD from three separate experiments.
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f1-cancers-03-00662: In vitro cytotoxicity of Fluvastatin and Zoledronic acid. T24 cells were exposed to a range of concentrations of fluvastatin (0.1 to 50 μM) and zoledronic acid (0.1 to 125 μM) for 24 to 72 hours as indicated, control cells treated identically except without adding drugs, the percentage of alive cells were detected by SRB method. The cytotocxicity of both drugs appeared dose and time dependant, T24 cells are slightly more sensitive to fluvastatin than to zoledronic acid, with an IC50 of 2.67 ± 0.61 μM for fluvastatin and 5.35 ± 1.35 μM for zoledronic acid at 72 hours treatment. Data represent the mean ± SD from three separate experiments.

Mentions: Treatment of T24 cells with increasing concentrations of fluvastatin (0.1 to 100 μM) or zoledronic acid (0.1 to 100 μM) for 24–72 hours caused dose and time-dependent cell growth inhibition. T24 cells were slightly more sensitive to fluvastatin (IC50 2.67 ± 0.61 μM at 72 h) than to zoledronic acid (IC50 5.35 ± 1.35 μM at 72 h) (Figure 1).


Ras Isoprenylation and pAkt Inhibition by Zoledronic Acid and Fluvastatin Enhances Paclitaxel Activity in T24 Bladder Cancer Cells.

Li S, De Souza P - Cancers (Basel) (2011)

In vitro cytotoxicity of Fluvastatin and Zoledronic acid. T24 cells were exposed to a range of concentrations of fluvastatin (0.1 to 50 μM) and zoledronic acid (0.1 to 125 μM) for 24 to 72 hours as indicated, control cells treated identically except without adding drugs, the percentage of alive cells were detected by SRB method. The cytotocxicity of both drugs appeared dose and time dependant, T24 cells are slightly more sensitive to fluvastatin than to zoledronic acid, with an IC50 of 2.67 ± 0.61 μM for fluvastatin and 5.35 ± 1.35 μM for zoledronic acid at 72 hours treatment. Data represent the mean ± SD from three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3756383&req=5

f1-cancers-03-00662: In vitro cytotoxicity of Fluvastatin and Zoledronic acid. T24 cells were exposed to a range of concentrations of fluvastatin (0.1 to 50 μM) and zoledronic acid (0.1 to 125 μM) for 24 to 72 hours as indicated, control cells treated identically except without adding drugs, the percentage of alive cells were detected by SRB method. The cytotocxicity of both drugs appeared dose and time dependant, T24 cells are slightly more sensitive to fluvastatin than to zoledronic acid, with an IC50 of 2.67 ± 0.61 μM for fluvastatin and 5.35 ± 1.35 μM for zoledronic acid at 72 hours treatment. Data represent the mean ± SD from three separate experiments.
Mentions: Treatment of T24 cells with increasing concentrations of fluvastatin (0.1 to 100 μM) or zoledronic acid (0.1 to 100 μM) for 24–72 hours caused dose and time-dependent cell growth inhibition. T24 cells were slightly more sensitive to fluvastatin (IC50 2.67 ± 0.61 μM at 72 h) than to zoledronic acid (IC50 5.35 ± 1.35 μM at 72 h) (Figure 1).

Bottom Line: Western blots were used to assess effects on signal transduction pathways.Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment.Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition.

View Article: PubMed Central - PubMed

Affiliation: Cancer Pharmacology and Therapeutics Laboratory, St George Hospital, Kogarah, NSW, Australia. p.desouza@unsw.edu.au.

ABSTRACT

Background: Bisphosphonates interfere with the mevalonate pathway and inhibit the prenylation of small GTP-binding proteins such as ras and rap. We hypothesized that zoledronic acid would synergistically inhibit T24 bladder cancer cell growth in combination with fluvastatin and paclitaxel.

Methods: Increasing doses of fluvastatin, zoledronic acid, and paclitaxel were investigated as single agents and in combination, and synergistic interactions were evaluated by the Chou-Talalay method. Western blots were used to assess effects on signal transduction pathways.

Results: Growth of T24 was significantly inhibited with IC50 values of 2.67 ± 0.61 mM for fluvastatin and 5.35 ± 1.35 mM for zoledronic acid after 72 hours treatment. Geranylgeranyl pyrophosphate and farnesyl pyrophosphate was able to block, in part, this inhibitory activity. The combinations of zoledronic acid and paclitaxel, zoledronic acid and fluvastatin, and fluvastatin and paclitaxel were all synergistic. Both fluvastatin and zoledronic acid inhibited Ras and Rap prenylation, and the phosphorylation of ERK1/2 and AKT. The degree of inhibition of phosphorylation of these key signaling transduction pathways appears to closely correlate with their synergistic interactions.

Conclusions: Zoledronic acid enhances fluvastatin and paclitaxel activity against T24 in a synergistic manner and this is mediated largely by inhibition of both the Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways via isoprenylation inhibition.

No MeSH data available.


Related in: MedlinePlus