African cactiform Hoodia gordonii (Asclepiadaceae) has been used for thousands of years by Xhomani Bushmen as an anorexant during hunting trips and has been proposed as a new agent for the management of body weight. However, its in vivo targets and molecular mechanisms remain elusive. GPR119, a G protein-coupled receptor highly expressed in pancreatic β cells and intestinal L cells, has been demonstrated to facilitate glucose-stimulated insulin secretion (GSIS) and represents a novel and attractive target for the therapy of metabolic disorders. Here, we disclose that Gordonoside F (a steroid glycoside isolated from H. gordonii), but not the widely known P57, activates specifically GPR119. Successful synthesis of Gordonoside F facilitates further characterization of this compound. Gordonoside F promotes GSIS both in vitro and in vivo and reduces food intake in mice. These effects are mediated by GPR119 because GPR119 knockout prevents the therapeutic effects of Gordonoside F. Interestingly, the appetite-suppressing effect of Hoodia extract was also partially blocked by GPR119 knockout. Our results demonstrate for the first time, to our knowledge, that GPR119 is a direct target and one of the major mechanisms underlying the therapeutic effect of the popular "weight loss" herb H. gordonii. Given the long history of safe application of this herb in weight control, it is foreseeable that the novel scaffold of Gordonoside F provides a promising opportunity to develop new drugs in treating metabolic diseases.

It is well known that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10) is specifically expressed in various tumor cells, but less or no expression in most normal tissues and cells. While TRAIL engages with its native death receptors, TRAIL receptor 1 (TRAIL-R1) or 2 (TRAIL-R2), usually elicits the tumor cell death by apoptosis. In this study, we report that a novel humanized monoclonal antibody against TRAIL-R2 (named as zaptuzumab) well remain the biological activity of the parental mouse antibody AD5-10 inducing cell death in various cancer cells, but little effect on normal cells. Zaptuzumab also markedly inhibited the tumor growth in the mouse xenograft of NCI-H460 without toxicity to the liver and kidney, and the efficacy of tumor suppression was increased significantly while it combined with cis-dichlorodiamineplatinum. Especially, I-labeled zaptuzumab injected into mouse tail vein specifically targeted to the xenograft of the lung cancer cells. Confocal analysis showed that zaptuzumab bound with TRAIL-R2 on cell surface could be quickly internalized and transferred into the lysosome. Furthermore, zaptuzumab possessed a high level of antibody-dependent cytotoxicity as well as complement-dependent cytotoxicity. Study on the mechanisms of cell death induced by zaptuzumab showed that it efficiently induced both caspase-dependent apoptosis and autophagic cell death. These data suggest that the humanized anti-TRAIL-R2 monoclonal antibody or the second generation of the antibody may have an important clinical usage for cancer immunotherapy. © 2017 IUBMB Life, 69(9):735-744, 2017.

It is well known that tumor necrosis factor-related apoptosis inducing ligand receptor 1 or 2 (DR4/DR5) is specifically expressed in various tumor cells, but less or no expression in most normal cells. Many first generations of TRAIL agonists including recombinant preparations of TRAIL, agonistic antibodies against DR4/DR5 have been developed in phase I/II clinical trials for cancer therapy. However, the outcomes of clinical trials by using DR4/DR5 agonist mono-therapy were disappointed even though the safety profile was well tolerance. In the present study, we report an anti-DR5 antibody-drug conjugate (ADC, named as Zapadcine-1) possesses a higher potential for the therapy of lymphocyte leukemia and solid cancers. Methods: Zapadcine-1 was made by a fully humanized DR5-specific monoclonal antibody (Zaptuzumab) coupled via a cleavable linker to a highly toxic inhibitor of tubulin, monomethyl auristatin D (MMAD), by using ThioBridge technology. Cytotoxicity of the ADC in various tumor cells was identified by luminescent cell viability assay and the efficacy in vivo was determined in cells derived xenografts (CDX) of Jurkat E6-1, BALL-1, Reh, and patient derived xenografts (PDX) of human acute leukemia. Preliminary safety evaluation was carried out in rat and monkey. Results: Zapadcine-1 possesses a similar binding ability to the death receptor DR5 as the naked monoclonal antibody Zaptuzumab, and can be rapidly endocytosed into the lysosome of cancer cells. Zapadcine-1 specifically kills human lymphocyte leukemia cells and solid tumor cells, but not normal cells tested. More importantly, Zapadcine-1 drastically eliminates the xenografts in both CDX and PDX models of human acute leukemia. The excellent and comparable therapeutic efficacy is also observed in lung cancer NCI-H1975 CDX mouse model. The maximum-tolerated dose (MTD) of single injected Zapadcine-1 in rat and cynomolgus monkey shows an acceptable safety profile. Conclusion: These data demonstrate a promising anti-cancer activity, meriting further exploration of its potential as a novel cancer therapeutic agent, especially for the acute lymphocyte leukemia.