Bisphosphonate zoledronic acid enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells.
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 microM) that induced G0/G1 arrest and zoledronate (50 microM) 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 microg/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.
Chang
John Wen-Cheng
JW
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
Hsieh
Jia-Juan
JJ
Shen
Yung-Chi
YC
Yeh
Kun-Yun
KY
Wang
Cheng-Hsu
CH
Li
Ying-Ying
YY
Hsu
Todd
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004164:Diphosphonates / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D063065:Organophosphonates; D011799:Quinazolines; D000077211:Zoledronic Acid; D066246:ErbB Receptors; D000077156:Gefitinib