Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells

Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1(st) Medical Department, Hanusch Hospital, Vienna, Austria.
Biochemical pharmacology (Impact Factor: 5.01). 10/2012; 85(2). DOI: 10.1016/j.bcp.2012.10.016
Source: PubMed


There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. By contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway.

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    • "However, as DAPK1 is involved in FAS-induced extrinsic apoptosis in lymphoid cells [88] and mediates the proapoptotic activity of TNF-␣ and INF-␥ (interferon-gamma) via the NF-␬B signaling pathways [89], there is no doubt considering a crucial contribution of this gene in the proapoptotic machinery as effected by demethylating drugs and histone-deacetylase inhibitors. In addition, FAS expression plays a critical role for AZA-induced and DAC-induced apoptosis as shown by siRNA experiments [90] and an increasing number of in vitro studies [22] [91]. In the present overview, we show that both FAS and DAPK1 are critical death regulators in neoplastic cells of MDS and AML. "
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