Zoledronic acid increases the antitumor effect of gefitinib treatment for non-small cell lung cancer with EGFR mutations.
Non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations and bone metastases are often concurrently administered tyrosine kinase inhibitors (TKIs) and bisphosphonates. Yet, the effects and mechanisms of these agents are unclear. In the present study, we aimed to ascertain whether zoledronic acid (ZA) increases the antitumor effects of gefitinib treatment on NSCLC with EGFR mutations and the related mechanisms of action. The effects of ZA and gefitinib on NSCLC tumor cells with EGFR mutations (HCC827, HCC827 GR and H1975) in regards to proliferation, apoptosis, cell cycle and signaling pathways were detected. ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance in vitro. Gefitinib caused cell cycle arrest in the G0/G1 phase, ZA induced S phase accumulation and the effect of the combined treatment was neutralization. Combined treatment obviously inhibited STAT3 and/or p‑STAT3 protein expression compared with treatment with each single drug in vitro and in vivo, and it also significantly inhibited TKI resistance NSCLC tumor growth in vivo. In conclusion, ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance by regulating the cell cycle, inducing caspase-3 expression and inhibiting STAT3 expression.
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Chengjun
C
Feng
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Xiaoke
X
Liu
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Xiaoyu
X
Li
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Fuchun
F
Guo
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Chuying
C
Huang
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Qing
Q
Qin
Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Yongsheng
Y
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077211:Zoledronic Acid; D066246:ErbB Receptors; D000077156:Gefitinib