title: N,N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) suppresses the proliferation of PANC-1 pancreatic cancer cells via apoptosis and G2/M cell cycle arrest.
abstract: Pancreatic cancer is one of the human gastrointestinal malignancies with a high mortality and poor prognosis. Approximately eighty percent of patients are diagnosed with unresectable or metastatic disease. Thus, development of novel chemicals in the treatment of pancreatic cancer is imperative. This study aimed to investigate the anticancer effects of N,N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1), a new tetrazine derivative, on the PANC-1 pancreatic cancer cell line and clarify the underlying molecular mechanism. Using an MTT assay, we found that ZGDHu-1 significantly suppressed the proliferation of PANC-1 cells in a time- and dose-dependent manner. Moreover, according to the morphological and flow cytometric analysis, the results indicated that ZGDHu-1 induced PANC-1 cell apoptosis and G2/M cell cycle arrest in a dose-dependent manner. In the western blot analysis, expression of the pro-apoptotic Bax gene was upregulated while the anti-apoptotic Bcl-2 gene was downregulated following treatment with ZGDHu-1. ZGDHu-1 also activated pro-caspase-3 and PARP and increased the expression of NF-κB inhibitor IκB. Furthermore, the expression levels of G2/M regulatory molecules such as cyclin B1 and cdc2 were decreased while that of Chk1 was increased. These results suggested that ZGDHu-1 suppressed the proliferation of pancreatic cancer cells, rendering it a potential therapeutic drug for the treatment of pancreatic cancer.
authors: Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China.
authors: Su-Feng
authors: SF
authors: Chen
authors: Clinical Laboratory Center, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, P.R. China.
authors: Jun
authors: J
authors: Xia
authors: College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, P.R. China.
authors: Ya-Ping
authors: YP
authors: Lv
authors: Clinical Laboratory Center, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, P.R. China.
authors: Jin-Lin
authors: JL
authors: Liu
authors: Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China.
authors: Wan-Xiang
authors: WX
authors: Li
authors: Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China.
authors: Xi-Ping
authors: XP
authors: Yu
authors: College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, P.R. China.
authors: Wei-Xiao
authors: WX
authors: Hu
authors: Clinical Laboratory Center, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, P.R. China.
authors: Yong-Lie
authors: YL
authors: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002277:Carcinoma / Q000473:pathology*; D053148:Caspase 3 / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D006573:Heterocyclic Compounds, 1-Ring; C522668:N,N-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxamide; D009363:Neoplasm Proteins; C505407:CASP3 protein, human; D053148:Caspase 3