机构:[1]Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Hong Kong, Peoples R China;[2]Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China;其他部门华南肿瘤学国家重点实验室中山大学肿瘤防治中心[3]Chinese Univ Hong Kong, Sch Pharm, Area 39, Room 801N, Shatin, Hong Kong, Peoples R China
Objectives: To investigate and elucidate the mechanism for the potentiation of cisplatin anticancer activity by belinostat in platinum (Pt)-resistant lung cancer cells. Materials and methods: Combination of cisplatin and belinostat was investigated in two pairs of parental and cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. The Pt-resistant cell models exhibited overexpression of the efflux transporter ABCC2 and enhanced DNA repair capacity. Cellular accumulation of cisplatin and extent of DNA platination were measured by inductively coupled plasma optical emission spectrometer. Expression of Pt transporters and DNA repair gene were determined by quantitative realtime PCR. Inhibition of ABCC2 transport activity was examined by flow cytometric assay. Regulation of ABCC2 at the promoter level was studied by chromatin immunoprecipitation assay. Results and conclusion: In Pt-resistant lung cancer cells, belinostat apparently circumvent the resistance through inhibition of both ABCC2 and DNA repair-mediated mechanisms. The combination of belinostat and cisplatin were found to display synergistic cytotoxic effect in cisplatin-resistant lung cancer cell lines when the two drugs were added concomitantly or when belinostat was given before cisplatin. Upon the concomitant administration of belinostat, cellular accumulation of cisplatin and formation of DNA-Pt adducts were found to be increased whereas expression levels of the efflux transporter ABCC2 and the DNA repair gene ERCC1 were inhibited in Pt-resistant cells. Belinostat-mediated downregulation of ABCC2 was associated with an increase association of a transcriptional repressor (negative cofactor 2) but reduced association of a transcriptional activator (TFIIB) to the ABCC2 promoter. The data advocates the use of belinostat as a novel drug resistance reversal agent for use in combination cancer chemotherapeutic regimens. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
基金:
CUHK Direct Grant for Research [4054207]
语种:
外文
被引次数:
WOS:
中科院(CAS)分区:
出版当年[2017]版:
大类|2 区医学
小类|2 区呼吸系统3 区肿瘤学
最新[2023]版:
大类|2 区医学
小类|3 区肿瘤学3 区呼吸系统
第一作者:
第一作者机构:[1]Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Hong Kong, Peoples R China;
通讯作者:
通讯机构:[1]Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Hong Kong, Peoples R China;[3]Chinese Univ Hong Kong, Sch Pharm, Area 39, Room 801N, Shatin, Hong Kong, Peoples R China
推荐引用方式(GB/T 7714):
To Kenneth Kin-Wah,Tong Wing-Sum,Fu Li-wu.Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat[J].LUNG CANCER.2017,103:58-65.doi:10.1016/j.lungcan.2016.11.019.
APA:
To, Kenneth Kin-Wah,Tong, Wing-Sum&Fu, Li-wu.(2017).Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat.LUNG CANCER,103,
MLA:
To, Kenneth Kin-Wah,et al."Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat".LUNG CANCER 103.(2017):58-65