Non-toxic dose chidamide synergistically enhances platinum-induced DNA damage responses and apoptosis in Non-Small-Cell lung cancer cells.
Combination of low doses of histone deacetylases inhibitors and chemotherapy drugs is considered as one of the most promising strategies to increase the anticancer efficacy. Chidamide is a novel benzamide chemical class of HDAC inhibitor that selectively inhibited HDAC1, 2, 3 and 10. We sought to determine whether chidamide may enhance platinum-induced cytotoxicity in NSCLC cells. In this study, the combination of chidamide with carboplatin showed a good synergism on growth inhibition with the mean combination index value as 0.712 and 0.639 in A549 and NCI-H157 cells, respectively. The used concentration of chidamide was non-toxic on cells by itself as low as 0.3μM. All of our experiments were comparisons between combination regimen and single carboplatin regimen in A549 and NCI-H157 cell lines. Phosphorylated histone H2A.X (γH2A.X), a hall marker of DNA damage response, was dramatically increased by the combination treatment. Cell cycle analysis by flow cytometry and phosphorylation level analysis of histone H3 (Ser10) by western blotting showed that combination treatment significantly increased the percentage of G2/M phase of cells. Mitochondrial membrane potential and cleaved-PARP1 level analysis indicate that chidamide synergistically enhances carboplatin-induced apoptosis. Additionally, synergistic effects of chidamide were found when it was combined with two other platinum drugs (cisplatin and oxaliplatin). The results suggest that Chidamide in combination with platinum drugs may be a novel therapeutic option for NSCLC.
Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, 518036 Guangdong, China; Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
You
Y
Zhou
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
De-Si
DS
Pan
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
Song
S
Shan
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
Jing-Zhong
JZ
Zhu
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
Kun
K
Zhang
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
Xu-Peng
XP
Yue
Department of Clinical Laboratory, Shenzhen Hospital, Peking University, Guangdong, China.
Li-Ping
LP
Nie
Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, 518036 Guangdong, China.
Jun
J
Wan
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
Xian-Ping
XP
Lu
Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, 518036 Guangdong, China. Electronic address: zhangweispace@yeah.net.
Wei
W
Zhang
Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China. Electronic address: zqning@chipscreen.com.
Zhi-Qiang
ZQ
Ning
D000631:Aminopyridines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin
D000631:Aminopyridines; D001549:Benzamides; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; D016190:Carboplatin; D002945:Cisplatin
Carboplatin; Cisplatin; DNA damage; HDAC inhibitor; Non-small-cell lung cancer; Oxaliplatin