Phenethyl isothiocyanate (PEITC) is an isothiocyanate that largely exists in cruciferous vegetables and exhibits chemopreventive and chemotherapeutic potential against various cancers. However, it is little known about the molecular mechanisms of its antitumor action against osteosarcoma, which is the second highest cause of cancer-related death in children and adolescents. In this study, we investigated the effects of PEITC on K7M2 murine osteosarcoma both in vitro and in vivo. We found that treatment with PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an IC 50 value of 33.49 μM at 24 h. PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G 2 /M cell cycle arrest, depleted glutathione (GSH), generated reactive oxygen species (ROS), altered iron metabolism, and triggered multiple forms of cell death, namely ferroptosis, apoptosis, and autophagy in K7M2 cells. We further revealed that PEITC treatment activated MAPK signaling pathway, and ROS generation was a major cause of PEITC-induced cell death. In a syngeneic orthotopic osteosarcoma mouse model, administration of PEITC (30, 60 mg/kg every day, ig, for 24 days) significantly inhibited the tumor growth, but higher dose of PEITC (90 mg/kg every day) compromised its anti-osteosarcoma effect. Histological examination showed that multiple cell death processes were initiated, iron metabolism was altered and MAPK signaling pathway was activated in the tumor tissues. In conclusion, we demonstrate that PEITC induces ferroptosis, autophagy, and apoptosis in K7M2 osteosarcoma cells by activating the ROS-related MAPK signaling pathway. PEITC has promising anti-osteosarcoma activity. This study sheds light on the redox signaling-based chemotherapeutics for cancers.

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Hemp seed-derived inhibitors of dipeptidyl peptidase IV (DPP-IV) demonstrate potential as novel therapeutics for diabetes; however, their proteome and genome remain uncharacterized. We used multi-omics technology to mine peptides capable of inhibiting DPP-IV. First, 1261 and 1184 proteins were identified in fresh and dry hemp seeds, respectively. Simulated protease cleavage of dry seed proteins yielded 185,446 peptides for virtual screening to select the potential DPP-IV-inhibiting peptides. Sixteen novel peptides were selected according to their DPP-IV-binding affinity determined via molecular docking. In vitro DPP-IV inhibition assays identified the peptides LPQNIPPL, YPYY, YPW, LPYPY, WWW, YPY, YPF, and WS with half-maximal inhibitory concentration (IC 50 ) values lower than 0.5 mM, which were 0.08 ± 0.01, 0.18 ± 0.03, 0.18 ± 0.01, 0.20 ± 0.03, 0.22 ± 0.03, 0.29 ± 0.02, 0.42 ± 0.03, and 0.44 ± 0.09 mM, respectively. The dissociation constants (K D ) of the 16 peptides ranged from 1.50 × 10 −4 to 1.82 × 10 −7 M. Furthermore, Caco2 and INS-1 cell assays showed that all 16 peptides could efficiently inhibit DPP-IV activity and increase insulin and glucagon-like peptide-1 concentrations. These results demonstrate a well-established and efficient method to isolate food-derived therapeutic DPP-IV-inhibiting peptides.

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