Abstract
Zoledronic acid (ZA), a bisphosphonate used to prevent skeletal fractures in patients with cancers, was demonstrated to induce apoptosis in a number of cancer cells. Our previous study showed that ZA also induces autophagic cell death in metastatic prostate cancer cells. However, the clinical trials using ZA in the treatment of metastatic prostate cancer did not have a longer diseases-free period. Since most of ZA was attracted to the bone after administration, we hypothesized that local prostate cancer cells may evolve prosurvival pathways upon low concentration of ZA treatment. In this study, we investigated the inflammatory effects of ZA on osteolytic PC3 prostate cancer cell, since inflammation was reported to be related to cancer development and survival. Exposure of PC3 cells to various concentrations of ZA resulted in induction of apoptosis and autophagy. The expression of inflammatory biomarkers including interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and NF-κB was remarkably upregulated in response to ZA treatment in a dose- and time-dependent manner. The production of IL-6 was elevated upon ZA treatment. The antiapoptotic protein Bcl2 was increased with parallel increased level of IL-6. Our data suggest that treatment with low concentrations of ZA enhances the inflammatory profile and may serve as a prosurvival signaling pathway in PC3 cells.
Highlights
Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is predominately prescribed to cancer patients with bone resorptive diseases owing to metastasis
Anticancer property of ZA has been reported to consist of apoptosis or autophagy [11, 12]
We investigated whether ZA induces inflammatory responses in prostate cancer cells
Summary
Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is predominately prescribed to cancer patients with bone resorptive diseases owing to metastasis. ZA possesses great bone affinity and exerts interference effect on osteoclasts functions through inhibition of protein prenylation and induction of apoptosis [1, 2]. Since zoledronic acid is recognized to significantly decrease skeletal-related events in prostate cancer patients with bony metastasis, the medication has been suggested to be a standard treatment modality for patient in this group. Mechanisms by which ZA directly inhibits cancer growth include activation of autophagy and induction of apoptosis. Indirect anticancer effects of ZA involve activation of immune responses against cancer, inhibition of angiogenesis, and interference of cell-cell interactions with mesenchymal stem cells. The effect of ZA on cancer cells in the aspect of inflammatory response remains sketchy. We conducted a study with the hypothesis that osteolytic prostate cells (PC3) respond to ZA treatment by ISRN Pathology
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