Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species

被引:25
|
作者
Chen, Yen-Po [1 ,2 ]
Shih, Po-Chang [1 ,3 ]
Feng, Chien-Wei [4 ]
Wu, Chang-Cheng [1 ,5 ]
Tsui, Kuan-Hao [6 ,7 ]
Lin, You-Hsien [8 ,9 ]
Kuo, Hsiao-Mei [1 ,10 ]
Wen, Zhi-Hong [1 ,11 ]
机构
[1] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 80424, Taiwan
[2] Kaohsiung Armed Forces Gen Hosp, Dept Obstet & Gynecol, Kaohsiung 80284, Taiwan
[3] Kaohsiung Chang Gung Mem Hosp, Dept Neurosurg, Kaohsiung 83301, Taiwan
[4] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Obstet & Gynecol, Kaohsiung 80756, Taiwan
[5] Kaohsiung Armed Forces Gen Hosp, Dept Obstet & Gynecol, Zouying Branch, Kaohsiung 81342, Taiwan
[6] Kaohsiung Vet Gen Hosp, Dept Obstet & Gynecol, Kaohsiung 81341, Taiwan
[7] Natl Yang Ming Univ, Inst Clin Med, Dept Obstet & Gynecol, Taipei 11221, Taiwan
[8] Kaohsiung Municipal Tatung Hosp, Dept Internal Med, Kaohsiung 80145, Taiwan
[9] Kaohsiung Med Univ, Dept Med, Coll Med, Kaohsiung 80708, Taiwan
[10] Natl Sun Yat Sen Univ, Ctr Neurosci, Kaohsiung 80424, Taiwan
[11] Natl Sun Yat Sen Univ, Inst Med Sci & Technol, Kaohsiung 80424, Taiwan
关键词
pardaxin; mitophagy; mitochondria; reactive oxygen species; apoptosis; natural product; ovarian cancer; oxidative phosphorylation; autophagosome; mitochondrial membrane potential; SIGNALING PATHWAYS; AUTOPHAGY; DYNAMICS; DYSFUNCTION; FISSION; STRESS; FUSION; DRUGS; CELLS; ROS;
D O I
10.3390/antiox10121883
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Most ovarian cancer (OC) patients are diagnosed with stage III or higher disease, resulting in a poor prognosis. Currently, paclitaxel combined with carboplatin shows the best treatment outcome for OC. However, no effective drug is available for patients that do not respond to treatment; thus, new drugs for OC are needed. We evaluated the antimicrobial peptide, pardaxin, in PA-1 and SKOV3 cells. Pardaxin induced apoptosis as determined by MTT and TUNEL assays, as well as activation of caspases-9/3, Bid, t-Bid, and Bax, whereas Bcl-2 was downregulated. The IC50 values for pardaxin were 4.6-3.0 mu M at 24 and 48 h. Mitochondrial and intracellular reactive oxygen species (ROS) were overproduced and associated with disrupted mitochondrial membrane potential and respiratory capacity. Additionally, the mitochondrial network was fragmented with downregulated fusogenic proteins, MFN1/2 and L-/S-OPA1, and upregulated fission-related proteins, DRP1 and FIS1. Autophagy was also activated as evidenced by increased expression of autophagosome formation-related proteins, Beclin, p62, and LC3. Enhanced mitochondrial fragmentation and autophagy indicate that mitophagy was activated. ROS-induced cytotoxicity was reversed by the addition of N-acetylcysteine, confirming ROS overproduction as a contributor. Taken together, pardaxin demonstrated promising anticancer activity in OC cells, which warrants further preclinical development of this compound.
引用
收藏
页数:22
相关论文
共 50 条
  • [1] Reactive oxygen species in mitochondria-mediated cell death
    Orrenius, Sten
    DRUG METABOLISM REVIEWS, 2007, 39 (2-3) : 443 - 455
  • [2] Mitochondria-mediated Reactive Oxygen Species May Relate to Docosahexaenoic Acid-induced Apoptosis in Human Cervical Cancer Cells
    Lim, K.
    Jing, K.
    Shin, S.
    Jeong, S.
    Kim, N.
    Oh, H.
    Heo, J. Y.
    Park, J. I.
    Yoon, W. H.
    Hwang, B. D.
    EUROPEAN JOURNAL OF CANCER, 2012, 48 : S33 - S33
  • [3] Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
    Liang, Wenquan
    Cai, Aizhen
    Chen, Guozhu
    Xi, Hongqing
    Wu, Xiaosong
    Cui, Jianxin
    Zhang, Kecheng
    Zhao, Xudong
    Yu, Jiyun
    Wei, Bo
    Chen, Lin
    SCIENTIFIC REPORTS, 2016, 6
  • [4] Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
    Wenquan Liang
    Aizhen Cai
    Guozhu Chen
    Hongqing Xi
    Xiaosong Wu
    Jianxin Cui
    Kecheng Zhang
    Xudong Zhao
    Jiyun Yu
    Bo Wei
    Lin Chen
    Scientific Reports, 6
  • [5] Docosahexaenoic acid-induced apoptosis is directly linked to mitochondria-mediated reactive oxygen species production in human cervical cancer cells
    Jing, Kaipeng
    Shin, Soyeon
    Kim, Nayeong
    Jeong, Soyeon
    Oh, Hye-Rim
    Cho, Eun-Ah
    Park, Ji-Hoon
    Seo, Kang-Sik
    Heo, Jun-Young
    Han, Jeong-Su
    Park, Jong-Il
    Kweon, Gi-Ryang
    Park, Seung-Kiel
    Yoon, Wan-Hee
    Hwang, Byung-Doo
    Lim, Kyu
    CANCER RESEARCH, 2012, 72
  • [6] Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak
    Kim, Young-Ae
    Xiao, Dong
    Xiao, Hui
    Powolny, Anna A.
    Lew, Karen L.
    Reilly, Megan L.
    Zeng, Yan
    Wang, Zhou
    Singh, Shivendra V.
    MOLECULAR CANCER THERAPEUTICS, 2007, 6 (05) : 1599 - 1609
  • [7] Butyrate Inhibits Gastric Cancer Cells by Inducing Mitochondria-mediated Apoptosis
    Zhang, Ke
    Ji, Xiawei
    Song, Zhengyang
    Wu, Fangquan
    Qu, Yue
    Jin, Xiaofeng
    Xue, Xiangyang
    Wang, Fangyan
    Huang, Yingpeng
    COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING, 2023, 26 (03) : 630 - 638
  • [8] Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos
    Lee, Jeong Eun
    Park, Jae Hyeon
    Shin, In Chul
    Koh, Hyun Chul
    TOXICOLOGY AND APPLIED PHARMACOLOGY, 2012, 263 (02) : 148 - 162
  • [9] Avian Coronavirus Infectious Bronchitis Virus Activates Mitochondria-Mediated Apoptosis Pathway and Affects Viral Replication by Inducing Reactive Oxygen Species Production in Chicken HD11 Cells
    Han, Xiaoxiao
    Huang, Yuan
    Hao, Junli
    BIOLOGY-BASEL, 2024, 13 (07):
  • [10] Shikonin Stimulates Mitochondria-Mediated Apoptosis by Enhancing Intracellular Reactive Oxygen Species Production and DNA Damage in Oral Cancer Cells
    Biswal, Stuti
    Panda, Munmun
    Biswal, Bijesh Kumar
    JOURNAL OF CELLULAR BIOCHEMISTRY, 2025, 126 (01)