title: The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways.
abstract: The β-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of β-nitrostyrene in esophageal cancer remain unclear. Here, a β-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers. CYT-Rx20 decreased cell viability and migration through suppression of the PI3K/AKT and STAT3 pathways. Of note, the cytotoxicity and anti-migratory effect of CYT-Rx20 were enhanced by co-treatment with SC79 (AKT activator) or colivelin (STAT3 activator), suggesting the dependency of esophageal cancer cells on AKT and STAT3 for survival and migration, an oncogene addiction phenomenon. In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. In orthotopic esophageal cancer mouse model, decreased tumor growth and lung metastasis with reduced Ki-67 and phospho-STAT3 expression were observed in mice treated with CYT-Rx20. Together, our results suggest that CYT-Rx20 is a potential β-nitrostyrene-based anticancer compound against the tumor growth and metastasis of esophageal cancer.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Chiu
authors.affiliation: Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Su
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Hou
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chie-Hong
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ying-Fong
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Chinese Medicine and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shyng-Shiou F
authors.identifier: http://orcid.org/0000-0002-4753-788X
authors.initials: SF
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects*; D013343:Styrenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C512238:3-hydroxy-4-methoxy-beta-methyl-beta-nitrostyrene; D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013343:Styrenes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt