Received for publication July 13, 2006.
Revised October 18, 2006.
Accepted for publication October 18, 2006.

Zoledronic acid activates the DNA S phase checkpoint and induces osteosarcoma cell death characterized by AIF and EndoG translocation independently of p53 and Rb status

Abstract

The molecular mechanisms responsible for the cellular effects of the nitrogen containing bisphosphonate Zoledronic acid (Zol) was assessed on several osteosarcoma cell lines differing in their p53 and Rb status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol-effects on proliferation were due to cell cycle arrest in S and G2/M phases subsequent to the activation of the intra S DNA damage checkpoint with an increase of P-ATR, P-chk1, Wee1, P-cdc2 levels and a decrease of cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation and was characterized by nuclear alterations, increased Bax expression and reduced Bcl2 level. Furthermore, mitochondrial permeability was also upregulated by Zol, independently of p53 in association with the translocation of Apoptosis Inducing Factor (AIF) and Endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization, cells junctions, inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumor cells. We have demonstrated for the fisrt time that Zoledronic acid activated the DNA damage S phase checkpoint, the mitochondrial pathway via AIF and EndoG translocation, inhibited cell proliferation and induced cell death bypassing these potentials mutations. Therefore Zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents are ineffective.

Key words: Mechanisms of cell killing/apoptosis, Pharmacokinetics, metabolism and activation, Tumor suppressors, Cholesterol metabolism/lipoproteins

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