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

Anticancer Drugs. 2011 Jan;22(1):89-98. doi: 10.1097/CAD.0b013e3283400a05.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Animals
  • Cell Cycle / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinases / biosynthesis
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • Diphosphonates / antagonists & inhibitors
  • Diphosphonates / pharmacology*
  • Diterpenes / pharmacology
  • Down-Regulation / drug effects
  • E2F Transcription Factors / metabolism
  • Imidazoles / antagonists & inhibitors
  • Imidazoles / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mevalonic Acid / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Retinoblastoma Protein / metabolism
  • Zoledronic Acid
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / biosynthesis*
  • ras Proteins / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Diphosphonates
  • Diterpenes
  • E2F Transcription Factors
  • Imidazoles
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinase Inhibitor p27
  • Zoledronic Acid
  • geranylgeraniol
  • Cyclin-Dependent Kinases
  • ras Proteins
  • Mevalonic Acid