Chen Peng, Li Xuejie, Zhang Ruonan, Liu Shuiping, Xiang Yu, Zhang Mingming, Chen Xiaying, Pan Ting, Yan Lili, Feng Jiao, Duan Ting, Wang Da, Chen Bi, Jin Ting, Wang Wengang, Chen Liuxi, Huang Xingxing, Zhang Wenzheng, Sun Yitian, Li Guohua, Kong Lingpan, Chen Xiaohui, Li Yongqiang, Yang Zuyi, Zhang Qin, Zhuo Lvjia, Sui Xinbing, Xie Tian
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Holistic Integrative Pharmacy Institutes and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Theranostics. 2020 Apr 6;10(11):5107-5119. doi: 10.7150/thno.44705. eCollection 2020.
: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. : KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and β-elemene, a bioactive compound isolated from Chinese herb . Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected and . Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. : CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml β-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with β-elemene and cetuximab. , β-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of β-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of β-elemene in combination with cetuximab on KRAS mutant CRC cells. , co-treatment with β-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. : Our data for the first time suggest that the natural product β-elemene is a new ferroptosis inducer and combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.
RAS 突变限制了抗表皮生长因子受体（EGFR）单克隆抗体联合化疗对转移性结直肠癌（mCRC）患者的疗效。因此，新的细胞死亡形式聚焦于识别间接靶点以抑制 Ras 诱导的肿瘤发生。最近，越来越多的证据表明触发铁死亡在癌症治疗中具有潜力，特别是对于根除对传统疗法耐药的侵袭性恶性肿瘤。：用西妥昔单抗和 β-榄香烯（一种从中药中分离出的生物活性化合物）处理 KRAS 突变的结直肠癌细胞 HCT116 和 Lovo。检测铁死亡和上皮-间质转化（EMT）情况。建立原位结直肠癌动物模型，通过 IVIS 生物发光成像监测肿瘤生长。收集肿瘤组织以确定治疗后的铁死亡效应和 EMT 标志物的表达。：CCK-8 试验表明，在 KRAS 突变的结直肠癌细胞中，当 125 µg/ml 的 β-榄香烯与 25 µg/ml 的西妥昔单抗联合使用时可获得协同效应。AV/PI 染色表明用 β-榄香烯和西妥昔单抗处理后细胞死亡呈非凋亡模式。，β-榄香烯与西妥昔单抗联合使用可诱导 KRAS 突变的结直肠癌细胞中铁依赖性活性氧（ROS）积累、谷胱甘肽（GSH）耗竭、脂质过氧化、HO-1 和转铁蛋白上调，以及铁死亡负调控蛋白（GPX4、SLC7A11、FTH1、谷氨酰胺酶和 SLC40A1）下调。同时，β-榄香烯与西妥昔单抗联合治疗抑制细胞迁移并降低间质标志物（波形蛋白、N-钙黏蛋白、Slug、Snail 和 MMP-9）的表达，但促进上皮标志物 E-钙黏蛋白的表达。此外，铁死亡抑制剂而非其他细胞死亡抑制剂消除了 β-榄香烯与西妥昔单抗联合对 KRAS 突变的结直肠癌细胞的作用。，β-榄香烯与西妥昔单抗联合治疗抑制了 KRAS 突变肿瘤的生长和淋巴结转移。：我们的数据首次表明天然产物 β-榄香烯是一种新的铁死亡诱导剂，β-榄香烯与西妥昔单抗联合治疗通过诱导铁死亡和抑制 EMT 对 KRAS 突变的结直肠癌细胞敏感，这有望为患有 RAS 突变的结直肠癌患者提供一种前瞻性策略。
