R115777 (Zarnestra®)/Zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl‐2 and bad phosphorylation

Abstract

Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras-->Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation. Finally, ZOL/R115777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinoma cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.

42 Analysis of Molecular Mechanisms and Anti-Tumoral Effects of Zoledronic Acid in Breast Cancer Cells

“…We found MAPK and AKT was decreased significantly after exposure to 10 µM ZOL (Figure 2). Thus, as expected and previously reported with higher doses [40], also low doses of ZOL induced decrease of both MAPK and Akt activity, by which proliferation and the ability of tumor cells to expand .…”

The enhancement of radiosensitivity in human esophageal squamous cell carcinoma cells by zoledronic acid and its potential mechanism

“…Owning to a high affinity for mineralized bone, ZOL rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL inhibits farnesyl pyrophosphate synthase, consequently suppresses prenylation of small G-proteins such as Ras, Rho and Rab, reduces the signals they mediate, and thereby prevents malignant behaviors of cancer cells (Caraglia et al 2007). The clinical use of the potent ZOL has increased recently (Rosen et al 2003;Hirsh et al 2008;Eidtmann et al 2010).…”

Metronomic administration of Zoledronic Acid and Taxotere combination in castration resistant prostate cancer patients: Phase I ZANTE trial

“…8 Antitumor effects of ZOL have also been reported in in vivo models that mimic tumor-induced bone disease associated with several cancer types. [9][10][11][12] Moreover, ZOL has shown synergistic induction of apoptosis in vitro when combined with the planned 12 cycles of treatment, while 17 patients discontinued treatment earlier because of progression (13 patients), toxicity (2 patients) and refusal (2 patients).…”