Department of Internal Medicine & Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, South Korea.
Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Republic of Korea.
BMC Cancer. 2022 Mar 29;22(1):341. doi: 10.1186/s12885-022-09414-6.
Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs.
The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model.
αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment.
This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU-induced augmentation of CSCs via the Notch signaling pathway.
由于结肠癌干细胞（CSC）在化疗耐药性以及肿瘤复发和转移中发挥重要作用，因此针对 CSC 的靶向治疗已成为癌症治疗的一种复杂策略。α-倒捻子素（αM）已被证实对癌细胞具有抗增殖和促凋亡作用。本研究旨在评估 αM 对结直肠癌（CRC）CSC 的选择性抑制作用，以及对 5-氟尿嘧啶（5-FU）诱导的 CSC 的抑制作用。
通过细胞活力测定来确定 αM 的最佳浓度。通过球体形成测定和 CSC 标志物流式细胞术来评估 αM 介导的 CSC 抑制作用。通过 Western blot 分析和实时定量 PCR 来研究 αM 对 Notch 信号通路和结肠 CSC 的影响。使用异种移植小鼠模型研究 αM 与 5-FU 联合的体内抗癌疗效。
αM 抑制 HT29 和 SW620 细胞的细胞活力并减少球体数量。αM 处理降低了 CSC，并抑制了 5-FU 诱导的 CSC 增加在流式细胞术中。αM 以时间和剂量依赖性方式显著抑制 Notch 信号通路中的 Notch1、NICD1 和 Hes1。此外，αM 以类似于 DAPT 处理的方式减弱 HT29 细胞中的 CSC 标志物 CD44 和 CD133。在异种移植小鼠中，αM 组和 αM 加 5-FU 治疗组的肿瘤和 CSC 标志物均受到抑制。
本研究表明，低剂量的 αM 通过 Notch 信号通路抑制 CRC 中的 CSC，并抑制 5-FU 诱导的 CSC 增加。
