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

被引：15

作者：

Urade, Ritesh ^{[1
,2
]}

Chang, Wen-Tsan ^{[3
,4
]}

Ko, Ching-Chung ^{[5
,6
]}

Li, Ruei-Nian ^{[7
]}

Yang, Hui-Min ^{[2
]}

Chen, Hsuan-Yu ^{[8
]}

Huang, Lin-Ya ^{[8
]}

Chang, Meng-Yang ^{[9
]}

Wu, Chang-Yi ^{[1
,2
]}

Chiu, Chien-Chih ^{[1
,2
,10
,11
,12
]}

机构：

[1] Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 804, Taiwan

[2] Kaohsiung Med Univ, Dept Biotechnol, Kaohsiung 807, Taiwan

[3] Kaohsiung Med Univ Hosp, Dept Surg, Div Gen & Digest Surg, Kaohsiung 807, Taiwan

[4] Kaohsiung Med Univ, Coll Med, Sch Med, Dept Surg, Kaohsiung 807, Taiwan

[5] Chi Mei Med Ctr, Dept Med Imaging, Tainan 71004, Taiwan

[6] Chia Nan Univ Pharm & Sci, Dept Hlth & Nutr, Tainan 717, Taiwan

[7] Kaohsiung Med Univ, Dept Biomed Sci & Environm Biol, Kaohsiung 807, Taiwan

[8] Kaohsiung Med Univ, Dept Med, Kaohsiung 807, Taiwan

[9] Kaohsiung Med Univ, Dept Med & Appl Chem, Kaohsiung 807, Taiwan

[10] Natl Appl Res Labs, Natl Lab Anim Ctr, Taipei 115, Taiwan

[11] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung 807, Taiwan

[12] Kaohsiung Med Univ, Ctr Canc Res, Kaohsiung 807, Taiwan

来源：

LIFE SCIENCES | 2023年 / 329卷

关键词：

Hepatocellular carcinoma (HCC); Fluorene derivative MSDF; ROS generation; Apoptosis; Anoikis; Autophagy; Immune checkpoint proteins; POLY(ADP-RIBOSE) POLYMERASE; PATHWAYS; PROLIFERATION; CHEMOTHERAPY; ACTIVATION; EXPRESSION; STRATEGIES; CLEAVAGE; SURVIVAL; ASSAY;

D O I：

10.1016/j.lfs.2023.121835

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 scav-enger. 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.

引用

页数：12

共 70 条

[11] Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer [J].