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

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.

Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells

“…These compounds, including OSI-027 [25, 39], AZD-8055 [40], AZD-2014 [18, 28] and XL388 [41], directly inhibit mTOR kinase to block activity of both mTORC1 and mTORC2 [37, 38]. Here, we show that CZ415 blocked mTORC1 and mTORC2 activation, but failed to induce feedback AKT and ERK activation.…”

Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response

“…Preclinical in vitro and in vivo studies from Tagaram et al showed a significant antiproliferative effect of C6‐ceramide: Adding C6‐ceramide to SK‐HEP1 cells in vitro ensued pro‐apoptotic effects, while SK‐HEP1 engrafted athymic mice treated with C6‐ceramide intravenously showed decreased tumour vascularization and proliferation compared to non‐treated mice . In preclinical trials Liu et al demonstrated that C6‐ceramide is able to significantly potentate the anti‐HCC effects of AZD‐8055, a dual inhibitor of a mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) . Regarding cellular mechanisms, Colombini et al revealed that especially C2‐ and C16Cer have the ability to perforate lipid biolayers, mainly the outer mitochondrial membranes, by forming water‐filled channels .…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…Short-chain ceramides have proven to be synergistic with docetaxel, doxorubicin, methotrexate and pemetrexed (antifolates) in murine melanoma cell lines, and osteosarcoma (Chapman et al, 2011; Feng, Li, Liu, Yang, & Zhang, 2014; Zhai, Sun, Han, Jin, & Zhang, 2015). Combining C 6 -ceramide with ACDase inhibitor (DM102), AZD-8055 (mTORC1/2 dual inhibitor), or AT406 (a small molecule IAP antagonist) was synergistically efficacious in breast cancer cell lines, hepatocellular carcinoma lines, or pancreatic cell lines and primary samples, respectively (Flowers et al, 2012; M. Liu, Gu, Guo, & Fan, 2016; Zhao, Sun, Zhang, Zhang, & Zhang, 2016).…”