Tumor Biology

, Volume 37, Issue 8, pp 11039–11048 | Cite as

C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor

Original Article

Abstract

Aberrant activation of mammalian target of rapamycin (mTOR) plays pivotal roles in promoting hepatocellular carcinoma (HCC) tumorigenesis and chemoresistance. Here, we tested the potential anti-HCC activity by a novel mTOR complex 1/2 (mTORC1/2) dual inhibitor AZD-8055 and, more importantly, the potential AZD-8055 sensitization effect by a cell-permeable short-chain ceramide (C6). We showed that AZD-8055 mainly exerted moderate cytotoxic effect against a panel of HCC cell lines (HepG2, Hep3B, and SMMC-7721). Co-treatment of C6 ceramide remarkably augmented AZD-8055-induced HCC cytotoxicity. Meanwhile, C6 ceramide dramatically potentiated AZD-8055-induced HCC cell apoptotic death. Further studies demonstrated that AZD-8055 and C6 ceramide synergistically induced anti-survival and pro-apoptotic activity in primary cultured human HCC cells, but not in the non-cancerous human hepatocytes. Signaling studies showed that AZD-8055 and C6 ceramide synergistically suppressed Akt-mTOR complex 1/2 cascade activation. In vivo, AZD-8055 oral administration suppressed HepG2 hepatoma xenograft growth in nude mice, while moderately improving mice survival. Its anti-tumor activity was dramatically potentiated with co-administration of a liposome-packed C6 ceramide. Together, these results demonstrate that concurrent targeting mTORC1/2 by AZD-8055 exerts anti-tumor ability in preclinical HCC models, and its activity is further sensitized with co-administration of C6 ceramide.

Keywords

Hepatocellular carcinoma (HCC) Mammalian target of rapamycin (mTOR) AZD-8055 C6 ceramide Chemo-sensitization 

Notes

Compliance with ethical standards

Human HCC tissue specimens were collected from three patients undergoing hepatectomy, with informed consents. All studies using human samples were conducted according to the principles expressed in the Declaration of Helsinki and national and international guidelines. The study was approved by the Ethics Review Board (ERB) of Xinjiang Medical University (No. 2014035).

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Intervention RadiologyThe Affiliated Tumor Hospital of Xinjiang Medical UniversityUrumqiChina
  2. 2.Department of Cancer Research InstituteThe Affiliated Tumor Hospital of Xinjiang Medical UniversityUrumqiChina

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