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 IC₅₀ value of 33.49 μM at 24 h. PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G₂/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.

苯乙基异硫氰酸酯（PEITC）是一种异硫氰酸酯，广泛存在于十字花科蔬菜中，对各种癌症具有化学预防和化学治疗的潜力。然而，对其骨肉瘤的抗肿瘤作用的分子机制知之甚少，而骨肉瘤是儿童和青少年癌症相关死亡的第二大原因。在这项研究中，我们调查了PEITC在体外和体内对K7M2鼠骨肉瘤的影响。我们发现用PEITC进行剂量依赖性抑制K7M2鼠骨肉瘤细胞的生存能力，在24 h时IC ₅₀值为33.49μM 。PEITC（1、15、30μM）剂量依赖性抑制细胞增殖，引起G ₂/ M细胞周期停滞，谷胱甘肽（GSH）耗尽，产生活性氧（ROS），铁代谢改变，并引发多种形式的细胞死亡，即K7M2细胞中的肥大性，凋亡和自噬。我们进一步揭示了PEITC治疗激活了MAPK信号通路，并且ROS的产生是PEITC诱导的细胞死亡的主要原因。在同基因异位骨肉瘤小鼠模型中，PEITC的给药（每天30，60 mg / kg，ig，连续24天）显着抑制了肿瘤的生长，但是更高剂量的PEITC（每天90 mg / kg）损害了其抗骨肉瘤的作用。组织学检查表明，在肿瘤组织中开始了多个细胞死亡过程，铁代谢改变并且MAPK信号传导途径被激活。总而言之，我们证明了PEITC会引起铁锈病，自噬，激活ROS相关的MAPK信号通路，促进K7M2骨肉瘤细胞凋亡和凋亡。PEITC具有有希望的抗骨肉瘤活性。这项研究揭示了基于氧化还原信号的癌症化学疗法。