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  3. The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121

The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121

  • Biochem Biophys Res Commun. 2015 Sep 11;465(1):137-44. doi: 10.1016/j.bbrc.2015.07.147.
Yi Peng 1,  Yajuan Zhou 1,  Long Cheng 2,  Desheng Hu 3,  Xiaoyi Zhou 3,  Zhaohua Wang 3,  Conghua Xie 4,  Fuxiang Zhou 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215001, China.
  • 3 Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
  • 4 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.
  • 5 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.
PMID: 26235881 DOI: 10.1016/j.bbrc.2015.07.147
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.

Keywords

Akt-mTOR signaling; Esophageal cancer; NFκB signaling; PP121.

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