In both LNCaP and PC-3 cells, R-568-induced cell death was found in a range of concentrations that are similar to the doses used signaling pathway in a recent report to induce apoptosis in isolated rat parathyroid cells [3]. The calcimimetic agents have been reported to increase intracellular calcium concentration in a dose-dependent manner [16], and calcium accumulation in mitochondria has been considered as a major apoptotic mechanism [reviewed in ref. [17]]. Thus, it is plausible that R-568 increased cytosolic calcium, leading to calcium accumulation and mitochondrial stress, eventually
resulting in apoptotic cell death. Further investigation in this aspect is underway by our group. CaSR signaling
has been studied in multiple cancers and different effects were reported depending on the cell types and agonists used [reviewed in ref. [18]]. For example, in parathyroid adenoma and colon cancers, loss of CaSR expression was reported, leading to uncontrolled growth due to elevated calcium level. In prostate cancers, calcium-mediated CaSR activation was reported to prevent apoptosis [19], and to stimulate www.selleckchem.com/products/abc294640.html cell proliferation [20], and to increase production of PTH-related protein (PTHrP), a causal factor in bone metastasis [9, 10]. On the other hand, CaSR-mediated apoptosis was also reported in osteoblast and human embryonic kidney cells [4, 21], especially the calcimimetic R-568-induced apoptotic cell death in hyperplastic parathyroid cells [3]. Consistently, in this study, we provided the first evidence that R-568 but not its negative
isomer S-568 induces apoptotic cell death in human prostate cancer cells, and that R-568-induced cell death is via a CaSR-dependent pathway. In conclusion, we demonstrated that the calcimimetic R-568 induces apoptotic cell death in prostate cancer cells. R-568-induced apoptotic cell death is via a mitochondria-related pathway. The usefulness of the calcimimetic agent in managing prostate cancer patients needs further testing in pre-clinical and clinical study. Acknowledgements We sincerely thank Amgen, Inc. for providing the NPS R-568 and S-568 reagents. Florfenicol This study was supported in part by KUMC William L. Valk Foundation, grants from KU Mason’s Foundation and KUMC Lied Foundation to Dr Benyi Li. References 1. Nagano N: Pharmacological and clinical properties of calcimimetics: calcium receptor activators that afford an innovative approach to controlling hyperparathyroidism. Pharmacol Ther 2006, 109: 339–365.CrossRefPubMed 2. Torres PU: Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease. J Ren Nutr 2006, 16: 253–258.CrossRefPubMed 3.