Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell car...Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway.展开更多
基金supported by funding from the National Natural Science Foundation of China(NSFC 81672659)。
文摘Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway.
