芴衍生物通过 ROS 介导的细胞凋亡、失巢凋亡和自噬抑制人肝癌细胞。

A fluorene derivative inhibits human hepatocellular carcinoma cells by ROS-mediated apoptosis, anoikis and autophagy.

机构信息

Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

出版信息

Life Sci. 2023 Sep 15;329:121835. doi: 10.1016/j.lfs.2023.121835. Epub 2023 Jun 8.

Abstract

Fluorene was previously reported to have anticancer activity against human cancer cells. In this study, we examined the in vitro function of 9-methanesulfonylmethylene-2, 3-dimethoxy-9 H -fluorene (MSDF), a novel fluorene derivative, its anticancer potential in human hepatocellular carcinoma (HCC) cells and its underlying molecular mechanism. The disruption of cellular homeostasis caused by MSDF was found to promote reactive oxygen species (ROS) generation, leading to the activation of cellular apoptosis. As a survival strategy, cells undergo autophagy during oxidative stress. MSDF-induced apoptosis occurred through both receptor-mediated extrinsic and mitochondrial-mediated intrinsic routes. The development of acidic vesicular organelles and the accumulation of LC3-II protein suggest an increase in the autophagic process. Apoptosis was detected by double staining. The MAPK/ERK and PI3K/Akt signaling pathways were indeed suppressed during treatment. Along with elevated ROS generation and apoptosis, MSDF also caused anoikis and cell death by causing cells to lose contact with their extracellular matrix. ROS production was induced by MSDF and sustained by an NAC scavenger. MSDF-induced apoptosis led to increased autophagy, as shown by the suppression of apoptosis by Z-VAD-FMK. However, inhibition of autophagy by inhibitor 3-MA increased MSDF-induced apoptosis. More evidence shows that MSDF downregulated the expression of immune checkpoint proteins, suggesting that MSDF could be used in the future as an adjuvant to improve the effectiveness of HCC immunotherapy. Altogether, our results highlight the potential of MSDF as a multitarget drug for the treatment of HCC.

摘要

芴曾被报道具有抑制人类癌细胞的抗癌活性。在这项研究中,我们研究了一种新型芴衍生物 9-甲磺酰亚甲基-2,3-二甲氧基-9H-芴(MSDF)在人肝癌(HCC)细胞中的体外功能及其潜在的分子机制。MSDF 破坏细胞内稳态,导致活性氧(ROS)的产生,从而激活细胞凋亡。作为一种生存策略,细胞在氧化应激下发生自噬。MSDF 诱导的细胞凋亡通过受体介导的外在途径和线粒体介导的内在途径发生。酸性囊泡细胞器的发育和 LC3-II 蛋白的积累表明自噬过程增加。通过双染色检测到凋亡。MAPK/ERK 和 PI3K/Akt 信号通路在治疗过程中确实受到抑制。随着 ROS 生成和凋亡的增加,MSDF 还通过使细胞失去与细胞外基质的接触而导致 anoikis 和细胞死亡。MSDF 诱导 ROS 的产生,并被 NAC 清除剂维持。MSDF 诱导的凋亡导致自噬增加,如 Z-VAD-FMK 抑制凋亡所显示的。然而,抑制剂 3-MA 抑制自噬增加了 MSDF 诱导的凋亡。更多证据表明,MSDF 下调免疫检查点蛋白的表达,这表明 MSDF 将来可作为辅助药物用于改善 HCC 免疫治疗的效果。总之,我们的研究结果强调了 MSDF 作为治疗 HCC 的多靶点药物的潜力。

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