Strusi Gabriele, Suelzu Caterina M, Horwood Nicole, Münsterberg Andrea E, Bao Yongping
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
School of Biological Sciences, University of East Anglia, Norwich, United Kingdom.
Front Pharmacol. 2023 Oct 4;14:1264032. doi: 10.3389/fphar.2023.1264032. eCollection 2023.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is among the most lethal tumours. Combination therapy exploits multiple drugs to target key pathways synergistically to reduce tumour growth. Isothiocyanates have been shown to possess anticancer potential and to complement the anticancer activity of other compounds. This study aimed to investigate the potential of phenethyl isothiocyanate (PEITC) to synergise with dasatinib, improving its anticancer potential in HCC. MTT, 3D spheroids and clonogenic assays were used to assess the combination anti-tumour effect , whereas a murine syngeneic model was employed to evaluate the combination efficacy . DCFDA staining was employed to evaluate the production of reactive oxygen species (ROS), while flow cytometry and Western blot assays were used to elucidate the molecular mechanism of the synergistic activiy. PEITC and dasatinib combination exhibited a synergistic effect and . The combination induced DNA damage and oxidative stress through the production of ROS, which led to the formation of a premature CDK1/Cyclin B1 complex associated with induction of mitotic catastrophe. Furthermore, ROS activated oxeiptosis, a caspase-independent form of programmed cell death. PEITC showed to enhance dasatinib action in treating HCC with increased production of ROS that induced cell cycle arrest followed by mitotic catastrophe, and to induce oxeiptosis. These results highlight the role that ITCs may have in cancer therapy as a complement of clinically approved chemotherapeutic drugs.
肝细胞癌（HCC）是最常见的肝癌类型，也是最致命的肿瘤之一。联合治疗利用多种药物协同作用于关键通路，以减少肿瘤生长。异硫氰酸盐已被证明具有抗癌潜力，并能增强其他化合物的抗癌活性。本研究旨在探讨异硫氰酸苯乙酯（PEITC）与达沙替尼协同作用的潜力，以提高其在HCC中的抗癌潜力。采用MTT法、3D球体法和克隆形成试验评估联合抗肿瘤效果，同时采用小鼠同基因模型评估联合疗效。采用DCFDA染色评估活性氧（ROS）的产生，同时采用流式细胞术和蛋白质免疫印迹试验阐明协同活性的分子机制。PEITC与达沙替尼联合使用表现出协同效应。该联合用药通过产生ROS诱导DNA损伤和氧化应激，导致与有丝分裂灾难诱导相关的早熟CDK1/细胞周期蛋白B1复合物的形成。此外，ROS激活了氧化程序性坏死，这是一种不依赖半胱天冬酶的程序性细胞死亡形式。PEITC显示出可增强达沙替尼治疗HCC的作用，增加ROS的产生，诱导细胞周期停滞，随后发生有丝分裂灾难，并诱导氧化程序性坏死。这些结果突出了异硫氰酸盐在癌症治疗中作为临床批准化疗药物补充剂可能发挥的作用。
