title: HZ08 reverse the aneuploidy-induced cisplatin-resistance in Gastric cancer by modulating the p53 pathway.
abstract: We evaluated the influence of DNA aneuploidy on chemotherapy-resistance in human Gastric cancer cell MKN45; we also evaluated the reversal effects of HZ08 on these cells and then preliminary investigated the possible involved pathway. We made use of a pair of human Gastric cancer cell dip-MKN45 (diploid MKN45) and aneu-MKN45 (aneuploid MKN45). Growth inhibition in response to chemotherapeutic drugs was evaluated by CellTiter-Glo Luminescent Cell Viability assay and clone formation assay. Flow cytometry and immuno-assay were applied to evaluate apoptosis and the expression of relative signaling molecules. MKN45 xenograft was generated to evaluate in vivo action. Aneu-MKN45 developed a resistance to cisplatin which could be reversed by HZ08; Flow cytometry and western-blot indicates that HZ08-combination could induce apoptosis and increase the expression of apoptosis-related biomarkers on aneu-MKN45; in vivo study also reflect the same correlation between aneuploidy and cisplatin-resistance, which could be antagonized by HZ08 combination; When investigating the involved pathway, in anue-MKN45, the expression of molecules in p53 pathway was decreased; HZ08 could increase the expression of p53 down-stream molecules as well as elevate the activity of p53, while inhibiting Mdm2, the major negative regulator of p53; p53 inhibitor Pifithrin-α could completely abrogate HZ08's synergism effects, and mimic cisplatin-resistance on dip-MKN45.Lower p53 pathway expression that attenuates cisplatin-induced apoptosis might be at least partly the reason of cisplatin-resistance occurred in aneuploid MKN45 both in vitro and in vivo; Combination of HZ08 could sensitize cisplatin-induced apoptosis through the activation of the p53 pathway, therefore represented a synergism effect on aneuploid MKN45 cells.
authors.affiliation: Department of Physiology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Shanghai ChemPartner Co., Ltd., No. 6 Building, 998 Halei Road, Zhangjiang Hi-Tech Park Pudong New Area, Shanghai 201203, China.
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Tang
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Chunhua
authors.initials: C
authors.lastname: Xu
authors.forename: Kedong
authors.initials: K
authors.lastname: Ouyang
authors.forename: Weirong
authors.initials: W
authors.lastname: Fang
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.forename: Fu
authors.initials: F
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Qin
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
keywords: Aneuploidy; Apoptosis; Cisplatin-resistance; Gastric cancer; HZ08; p53 pathway