Zoledronic acid induces cell-cycle prolongation in murine lung cancer cells by perturbing cyclin and Ras expression

Ying Ying Li, John W.C. Chang, Ying Chieh Liu, Cheng Hsu Wang, Hsin Ju Chang, Meng Chun Tsai, Shiawhwa Paul Su, Kun Yun Yeh*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

13 Scopus citations


Zoledronic acid (ZOL) was shown earlier to prolong survival in animal models of lung cancer. The aim of this study was to examine whether alteration of intracellular cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, retinoblastoma, and Ras protein expression and E2F localization are among the possible antilung cancer mechanisms driven by ZOL. Furthermore, we used geranylgeraniol to test whether the mevalonate pathway is involved in the antitumor effects of ZOL against lung cancer. Line-1 cells, a murine lung adenocarcinoma cell line, were examined. ZOL significantly slowed the growth of these cells both in vitro and in vivo. The ZOL-treated cells typically arrested at the S/G2/M phase of the cell cycle, accompanied by increased intracellular levels of cyclin A, B1, and CDC2 and decreased levels of cyclin D, p21, p27, phosphorylated retinoblastoma, and Ras. In addition, ZOL affected the distribution of E2F. When geranylgeraniol was added to the ZOL-treated cells, either in vitro or in vivo, tumor growth, cell-cycle progression, the expression of certain cyclins, and cyclin-related regulatory proteins were partially returned to that of untreated controls. Therefore, ZOL elicits cell-cycle prolongation that seems to be associated with alterations in the levels of certain cyclins and cyclin-related regulatory proteins. Furthermore, the mevalonate pathway regulates ZOL-induced murine lung cancer inhibition both in vitro and in vivo.

Original languageEnglish
Pages (from-to)89-98
Number of pages10
JournalAnti-Cancer Drugs
Issue number1
StatePublished - 01 2011


  • Ras protein
  • cell cycle
  • cyclins
  • lung cancer
  • zoledronic acid


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