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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

Reversal of cell growth inhibition induced by fluvastatin (Fluv) and zoledronic acid (Zol) with geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Control cells were maintained in growth medium and represent 100% cell growth. GGPP significantly rescues cell death from both drugs (P < 0.01, n = 3), but FPP only blocks cell growth inhibition induced by fluvastatin (P < 0.01, n = 3). There is no significant difference between zoledronic acid alone and zoledronic acid + FPP (P = 0.388, n = 3). Data represent the mean ± SD from three separate experiments.
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f2-cancers-03-00662: Reversal of cell growth inhibition induced by fluvastatin (Fluv) and zoledronic acid (Zol) with geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Control cells were maintained in growth medium and represent 100% cell growth. GGPP significantly rescues cell death from both drugs (P < 0.01, n = 3), but FPP only blocks cell growth inhibition induced by fluvastatin (P < 0.01, n = 3). There is no significant difference between zoledronic acid alone and zoledronic acid + FPP (P = 0.388, n = 3). Data represent the mean ± SD from three separate experiments.

Mentions: In these experiments, fluvastatin (3μM) and zoledronic acid (10μM) inhibited cell proliferation by 44 ± 6.2%, and 71 ± 2%, respectively (Figure 2). Geranylgeranyl pyrophosphate (GGPP, 10 μM) appeared to completely block T24 growth inhibition induced by the two drugs, with the proportion of surviving cells similar to control values (91 ± 8% for fluvastatin and 89 ± 6% for zoledronic acid). On the other hand, farneysl pyrophosphate (FPP) could only partially rescue the growth inhibition induced by fluvastatin (76.3 ± 4% of control) while leaving cytotoxicity of zoledronic acid unaffected (30 ± 5% of control). Growth inhibition by both fluvastatin and zoledronic acid could be rescued completely by adding GGPP and FPP in combination (98 ± 4% control for fluvastatin and 91 ± 5% control for zoledronic acid).


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)

Reversal of cell growth inhibition induced by fluvastatin (Fluv) and zoledronic acid (Zol) with geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Control cells were maintained in growth medium and represent 100% cell growth. GGPP significantly rescues cell death from both drugs (P < 0.01, n = 3), but FPP only blocks cell growth inhibition induced by fluvastatin (P < 0.01, n = 3). There is no significant difference between zoledronic acid alone and zoledronic acid + FPP (P = 0.388, n = 3). Data represent the mean ± SD from three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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

f2-cancers-03-00662: Reversal of cell growth inhibition induced by fluvastatin (Fluv) and zoledronic acid (Zol) with geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Control cells were maintained in growth medium and represent 100% cell growth. GGPP significantly rescues cell death from both drugs (P < 0.01, n = 3), but FPP only blocks cell growth inhibition induced by fluvastatin (P < 0.01, n = 3). There is no significant difference between zoledronic acid alone and zoledronic acid + FPP (P = 0.388, n = 3). Data represent the mean ± SD from three separate experiments.
Mentions: In these experiments, fluvastatin (3μM) and zoledronic acid (10μM) inhibited cell proliferation by 44 ± 6.2%, and 71 ± 2%, respectively (Figure 2). Geranylgeranyl pyrophosphate (GGPP, 10 μM) appeared to completely block T24 growth inhibition induced by the two drugs, with the proportion of surviving cells similar to control values (91 ± 8% for fluvastatin and 89 ± 6% for zoledronic acid). On the other hand, farneysl pyrophosphate (FPP) could only partially rescue the growth inhibition induced by fluvastatin (76.3 ± 4% of control) while leaving cytotoxicity of zoledronic acid unaffected (30 ± 5% of control). Growth inhibition by both fluvastatin and zoledronic acid could be rescued completely by adding GGPP and FPP in combination (98 ± 4% control for fluvastatin and 91 ± 5% control for zoledronic acid).

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