Induction of cancer cell-specific apoptosis via activation of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) signaling has been an attractive goal for cancer therapeutics. However, many tumor cells develop resistance to TRAIL. Therefore, the search for enhancers of TRAIL-induced apoptosis has accelerated over the past several years. A high-throughput screening assay was developed that identified several natural product enhancers of TRAIL-induced apoptosis in TRAIL-resistant renal carcinoma cells. Among these natural products was the protein synthesis inhibitor, rocaglamide A, a cyclopenta[b]benzofuran secondary metabolite from the genus Aglaia, with potent antiproliferative and anti-inflammatory properties. Natural and synthetic rocaglates have been reported to have potent anticancer activities in vitro on various human cancer cell lines and in vivo in mouse models. The mechanism of action involved in the anticancer effects of rocaglamide A is generally thought to be inhibition of translation initiation. However, several other cancer-related cellular effects including cell cycle arrest have been reported in various cancer cell types. In this study, rocaglamide A and its synthetic analogs were assessed for their ability to enhance TRAIL-induced apoptosis, inhibit protein synthesis, and regulate cellular processes associated with TRAIL sensitization in TRAIL-resistant ACHN renal carcinoma cells. Rocaglate treatment enhanced TRAIL signaling resulting in caspase-dependent apoptotic cell death upon addition of TRAIL. Rocaglates also inhibited protein synthesis, which correlates with rapid loss of the antiapoptotic FLICE-inhibitory protein (cFLIP) and MCL-1, which are often overexpressed in TRAIL-resistant cancer cells. On average, the rocaglates were ~4-5-fold more potent than TRAIL sensitizers compared to their protein synthesis inhibitory potency. This difference suggests a possible therapeutic window for induction of TRAIL sensitization while minimizing general effects of protein synthesis inhibition. Rocaglamide treatment alone inhibited cell proliferation leading to cell cycle arrest at G2/M phase but not subsequent apoptosis. These studies suggest that the TRAIL-sensitizing activity of rocaglates and their growth-inhibitory effects as single agents are largely dependent on protein synthesis inhibition. The development of a large number of structurally diverse but mechanistically similar enhancers of TRAIL signaling with a wide range of potencies allows for further understanding of structure-activity relationships regarding both protein synthesis inhibition and TRAIL sensitization for this important family of compounds.
Funded (in part) by NCI Contract No. HHSN261200800001E.
Citation Format: Ancy D. Nalli, Lauren E. Brown, Cheryl L. Thomas, Thomas J. Sayers, John A. Porco, Curtis J. Henrich. Rocaglamide A and synthetic analogues sensitize resistant renal carcinoma cells to TRAIL-induced apoptosis and inhibit cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3903.