The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation.
Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer.
Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, PR China.
Fan
F
Xie
Department of Oncology, Wuhan Union Hospital Affiliated to Huazhong University of Science and Technology, Wuhan, PR China.
Pengcheng
P
Li
Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, PR China.
Jianhua
J
Gong
Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, PR China.
Jiahong
J
Zhang
Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, PR China. Electronic address: mjpjzhospital@hotmail.com.
Jingping
J
Ma
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D017368:Protein Prenylation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
Bisphosphonate; Lung cancer; Prenylation; Ras signalling; Zoledronic acid