MDL-800,an allosteric activator of SIRT6,suppresses proliferation and enhances EGFR-TKIs therapy in non-small cell lung cancer  

作　　者：Jia-lin Shang Shao-bo Ning Ying-yi Chen Tian-xiang Chen Jian Zhang 

机构地区：[1]State Key Laboratory of Oncogenes and Related Genes,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Shanghai Lung Cancer Center,Shanghai Chest Hospital,Shanghai Jiao Tong University,Shanghai 200030,China [3]Medicinal Bioinformatics Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [4]School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmacologica Sinica》2021年第1期120-131,共12页中国药理学报（英文版）

基　　金：This research is sponsored by the National Natural Science Foundation of China(81925034,91753117,81721004 to JZ and 81901423 to YYC);Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036 to JZ);Shanghai Science and Technology Innovation(19431901600 to JZ);Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program(2018BR12 to JZ);Shanghai Health and Family Planning Commission(20184Y0268 to YYC).

摘　　要：Sirtuin 6(SIRT6),a member of the sirtuin family,is a nicotinamide adenine dinucleotide(NAD+)-dependent deacetylase that is involved in various physiological and pathological processes.SIRT6 is generally downregulated and linked to tumorigenesis in non-small cell lung carcinoma(NSCLC),thus regarded as a promising therapeutic target of NSCLC.In this study,we investigated whether MDL-800,an allosteric activator of SIRT6,exerted antiproliferation effect against NSCLC cells in vitro and in vivo.We showed that MDL-800 increased SIRT6 deacetylase activity with an EC50 value of 11.0±0.3μM;MDL-800(10–50μM)induced dose-dependent deacetylation of histone H3 in 12 NSCLC cell lines.Treatment with MDL-800 dose dependently inhibited the proliferation of 12 NSCLC cell lines with IC50 values ranging from 21.5 to 34.5μM.The antiproliferation effect of MDL-800 was significantly diminished by SIRT6 knockout.Treatment with MDL-800 induced remarkable cell cycle arrest at the G0/G1 phase in NSCLC HCC827 and PC9 cells.Furthermore,MDL-800(25,50μM)enhanced the antiproliferation of epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)in osimertinib-resistant HCC827 and PC9 cells as well as in patient-derived primary tumor cells,and suppressed mitogen-activated protein kinase(MAPK)pathway.In HCC827 cell-derived xenograft nude mice,intraperitoneal administration of MDL-800(80 mg·kg^(−1)·d^(−1),for 14 days)markedly suppressed the tumor growth,accompanied by enhanced SIRT6-dependent histone H3 deacetylation and decreased p-MEK and p-ERK in tumor tissues.Our results provide the pharmacological evidence for future clinical investigation of MDL-800 as a promising lead compound for NSCLC treatment alone or in combination with EGFR-TKIs.

关 键 词：non-small cell lung cancer SIRT6 activator MDL-800 DEACETYLATION EGFR-TKIS MAPK ERK 

分 类 号：R734.2[医药卫生—肿瘤]