The molecular mechanisms responsible for the cellular effects of the
nitrogen-containing
bisphosphonate zoledronic acid (Zol) were assessed on several
osteosarcoma cell lines differing in their p53 and
retinoblastoma (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 in P-ATR, P-chk1, Wee1, and P-cdc2 levels and a decrease in cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of
caspase activation, and it was characterized by nuclear alterations, increased Bax expression, and reduced Bcl-2 level. Furthermore, mitochondrial permeability was up-regulated by Zol independently of p53 in association with the translocation of
apoptosis-inducing factor (AIF) and
endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization and cell junctions and 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 signaling carried by many
tumor cells. We have demonstrated for the first time that
zoledronic acid activated the DNA damage S-phase checkpoint and the mitochondrial pathway via AIF and EndoG translocation, and it 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 is ineffective.