title: The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121.
abstract: Here we explored the potential effect of PP121, a novel dual inhibitor of tyrosine and phosphoinositide kinases, against human esophageal cancer cells. We showed that PP121 exerted potent cytotoxic effect in primary (patient-derived) and established (Eca-109, TE-1 and TE-3 lines) esophageal cancer cells, possibly through activating caspase-3-dependnent apoptosis. PP121 was, however, non-cytotoxic to the normal human esophageal epithelial cells (EECs). At the molecular level, we showed that PP121 blocked Akt-mTOR (mammalian target of rapamycin) activation in esophageal cancer cells, which was restored by introducing a constitutively-active Akt (CA-Akt). Yet, CA-Akt only partly inhibited cytotoxicity by PP121 in Eca-109 cells. Importantly, we showed that PP121 inhibited nuclear factor kappa B (NFκB) signaling activation in esophageal cancer cells, which appeared independent of Akt-mTOR blockage. In vivo, oral administration of PP121 remarkably inhibited Eca-109 xenograft growth in nude mice, and significantly improved mice survival. Further, the immunohistochemistry (IHC) and Western blot assays analyzing xenografted tumors showed that PP121 inhibited Akt-mTOR and NFκB activations in vivo. Together, we demonstrate that PP121 potently inhibits esophageal cancer cells in vitro and in vivo, possibly through concurrently inhibiting Akt-mTOR and NFκB signalings.
authors.affiliation: Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215001, China.
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: chxie_65@hotmail.com.
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: ZhouFuxiangwuhan@126.com.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C533409:PP121 compound; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3
keywords: Akt-mTOR signaling; Esophageal cancer; NFκB signaling; PP121