Bisphosphonate zoledronic acid enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells

John Wen Cheng Chang, Jia Juan Hsieh, Yung Chi Shen, Kun Yun Yeh, Cheng Hsu Wang, Ying Ying Li, Todd Hsu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

27 Scopus citations


Patients with non-small cell lung carcinoma (NSCLC) bearing epidermal growth factor receptor (EGFR) gene mutations are good responders to gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (EGFR-TKI), yet these patients may eventually develop acquired resistance to all available EGFR-TKIs. Nitrogen-containing bisphosphonates (N-BPs) are inhibitors of farnesyl diphosphate (FPP) synthase as well as chelators of divalent cations. This study was undertaken to examine if the N-BP zoledronic acid (zoledronate) possessing antitumor activity could enhance the antitumor effect of gefitinib on the HCC827 NSCLC cell line expressing mutated EGFR. Both gefitinib and zoledronate were cytotoxic to HCC827 cells when treated alone. Combined treatment with gefitinib (0.025 μM) that induced G0/G1 arrest and zoledronate (50 μM) that caused S/G2/M accumulation generated an additive induction in cell cytotoxicity, sub-G1 cell population, and apoptosis. Gefitinib suppressed EGF-activated phosphorylation of ERK1/2 and Akt, while zoledronate seemed to impose its pharmacological effect independent of ERK1/2 and Akt phosphorylation. The volumes of xenografted tumors in nude mice co-administered with gefitinib (1 mg/kg/day, five days a week, p.o.) and zoledronate (10 μg/kg, twice weekly, i.p.) were significantly smaller than those of tumors in mice treated with gefitinib alone at the last stage of a 6-week in vivo study. Severe peri-tumoral fat loss frequently observed in gefitinib-treated mice disappeared in mice receiving the combined treatment. Hence, combined treatment of gefitinib with zoledronate may form a basis to develop a more effective and less toxic therapy for NSCLC with EGFR gene mutations.

Original languageEnglish
Pages (from-to)17-26
Number of pages10
JournalCancer Letters
Issue number1
StatePublished - 08 06 2009


  • Gefitinib
  • Non-small cell lung carcinoma
  • Zoledronic acid


Dive into the research topics of 'Bisphosphonate zoledronic acid enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells'. Together they form a unique fingerprint.

Cite this