Aglaia Extract Rocaglamide Targets Solid Tumors And Overcomes Tumor Resistance

Part Ⅰ Targeting the prohibitin scaffold-CRAF kinase interaction in RAS-ERK-driven pancreatic ductal adenocarcinomaObjective:Robust ERK1/2activity, which frequently results from KRAS mutation, invariably occurs in pancreatic ductal adenocarcinoma (PDAC). However, direct interference of KRAS signaling has not led to clinically successful drugs. Correct localization of RAF is regulated by the scaffold protein prohibitin (PHB) that ensures the spatial organization between RAS and RAF in plasma membranes, thus leading to activation of downstream effectors. Here, we investigate the role of PHB in growth, invasion and metastasis of pancreatic ductal adenocarcinoma.Methods:PHB expression was analyzed in human pancreatic cancer cell lines, normal pancreas, and PDAC tissue. Furthermore, genetic ablation or pharmacological inhibition of PHB was performed to determine its role in growth, migration, and signaling of pancreatic cancer cells in vitro and in vivo.Results:The level of PHB expression was crucial for maintenance of oncogenic ERK-driven pancreatic tumorigenesis. Additionally, rocaglamide (RocA), a small molecular inhibitor, selectively bound to PHB with nanomolar affinity to disrupt the PHB-CRAF interaction by altering its localization to the plasma membrane. Consequently, there was an impairment of oncogenic RAS-ERK signaling, thereby blocking in vitro and in vivo growth and metastasis of pancreatic cancer cells that were addicted to RAS-ERK signaling. More importantly, RocA treatment resulted in a significant increase of the lifespan of tumor-bearing mice without any detectable toxicity.Conclusions:Blockade of the PHB scaffold-CRAF kinase interaction, which is distinct from direct kinase inhibition, may be a new therapeutic strategy to target oncogenic ERK-driven pancreatic cancer. Part Ⅱ Rocaglamide overcomes TRAIL resistance in hepatocellular carcinoma cells by uncoupling the inhibition of caspase-8through c-FLIP downregulationObjective:Enhancing apoptosis is a therapeutic strategy for cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit a major resistance to TRAIL-induced cell death. Here, we investigate whether rocaglamide sensitizes resistant HCC cells to TRAI-mediated apoptosis.Methods:HCC cell lines (HepG2and Huh-7) were treated with rocaglamide and/or TRAIL and detected by means of apoptosis and TRAIL signaling pathway. In vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts.Results:Rocaglamide significantly sensitized TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from rocaglamide-mediated downregulation of c-FLIP and then caspase-8activation. Furthermore, rocaglamide strongly blocked the growth of tumors from Huh-7cells propagated in SCID mice, suggesting that chemosentization also occurred in vivo.Conclusions:Taken together, our data suggest rocaglamide can synergize with TRAIL against TRAIL-resistant HCC cells. Thus, we conclude that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for HCC treatment.