Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China.
Cancer Chemother Pharmacol. 2018 Mar;81(3):469-481. doi: 10.1007/s00280-017-3507-2. Epub 2018 Jan 8.
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is generally resistant to chemotherapy. In the present study, the cytotoxic activity of Rabdocoestin B (Rabd-B) against ESCC and the underlying mechanisms were investigated.
The inhibitory effect of Rabd-B on KYSE30 and KYSE450 was evaluated by Cell Counting Kit-8 (CCK8) and colony formation assays in vitro. The cell cycle distribution and apoptosis of cells treated with Rabd-B were determined by flow cytometry. The mechanisms underlying the effects of Rabd-B were systematically examined by Western blot. The in vivo anti-tumor ability of Rabd-B was measured in mouse xenograft models and cisplatin (DDP) was used as positive control.
Rabd-B efficiently induced G2/M phase arrest in ESCC cells by upregulating the Chk1/Chk2-Cdc25C axis to inhibit the G2→M transition facilitated by Cdc2/Cyclin B1. Furthermore, Rabd-B suppressed ATM/ATR phosphorylation, thereby inhibiting BRCA1-mediated DNA repair, which resulted in mitotic catastrophe and induced cell apoptosis. Rabd-B also decreased the activity of the Akt and NF-κB survival signaling pathways and ultimately initiated the caspase-9-dependent intrinsic apoptotic pathway in ESCC cells. The apoptosis induced by Rabd-B could be partially reversed by a caspase-9-specific inhibitor (Z-LEHD-FMK) and a pan-caspase inhibitor (Z-VAD-FMK). Moreover, Rabd-B effectively suppressed tumor growth in mouse xenografts which was comparable to that of DDP without significant injuries to the mice.
Taken together, these findings indicate that Rabd-B is a promising precursor compound that may be useful as a treatment for ESCC and thus warrants further investigation.
食管鳞状细胞癌（ESCC）是最具侵袭性的鳞状细胞癌之一，通常对化疗有抗性。本研究旨在探讨 Rabdocoestin B（Rabd-B）对 ESCC 的细胞毒性作用及其潜在机制。
通过细胞计数试剂盒-8（CCK8）和体外集落形成实验评估 Rabd-B 对 KYSE30 和 KYSE450 的抑制作用。通过流式细胞术测定 Rabd-B 处理后细胞的细胞周期分布和凋亡情况。通过 Western blot 系统研究 Rabd-B 作用的机制。在小鼠异种移植模型中测量 Rabd-B 的体内抗肿瘤能力，并将顺铂（DDP）用作阳性对照。
Rabd-B 通过上调 Chk1/Chk2-Cdc25C 轴来抑制 Cdc2/Cyclin B1 促进的 G2→M 转换，从而有效地诱导 ESCC 细胞 G2/M 期阻滞。此外，Rabd-B 抑制 ATM/ATR 磷酸化，从而抑制 BRCA1 介导的 DNA 修复，导致有丝分裂灾难并诱导细胞凋亡。Rabd-B 还降低了 Akt 和 NF-κB 生存信号通路的活性，最终在 ESCC 细胞中启动了 caspase-9 依赖性内在凋亡途径。Rabd-B 诱导的凋亡可被 caspase-9 特异性抑制剂（Z-LEHD-FMK）和泛 caspase 抑制剂（Z-VAD-FMK）部分逆转。此外，Rabd-B 可有效抑制小鼠异种移植肿瘤的生长，其效果与 DDP 相当，而对小鼠无明显损伤。
综上所述，这些发现表明 Rabd-B 是一种很有前途的前体化合物，可作为 ESCC 的治疗药物，值得进一步研究。
