药学学报, 2019, 54(7): 1288-1296
引用本文:
杨璨羽, 王大宽, 邓海亮, 张华, 代文兵, 何冰, 张强, 孟祥豹, 王学清. 纳米化色胺酮类化合物CY-1-4诱导B16-F10细胞发生铁死亡[J]. 药学学报, 2019, 54(7): 1288-1296.
YANG Can-yu, WANG Da-kuan, DENG Hai-liang, ZHANG Hua, DAI Wen-bing, HE Bing, ZHANG Qiang, MENG Xiang-bao, WANG Xue-qing. Tryptanthrin derivative CY-1-4 nanoparticle induces ferroptosis in B16-F10 cells[J]. Acta Pharmaceutica Sinica, 2019, 54(7): 1288-1296.

纳米化色胺酮类化合物CY-1-4诱导B16-F10细胞发生铁死亡
杨璨羽1, 王大宽1, 邓海亮1, 张华1, 代文兵1, 何冰1, 张强1,2, 孟祥豹2, 王学清1
1. 北京大学药学院北京市分子制药与新药传递系统重点实验室, 北京 100191;
2. 北京大学药学院国家仿生药物与天然药物重点实验室, 北京 100191
摘要:
CY-1-4是一种色胺酮类化合物,其抗肿瘤作用已被证实,但其水溶性差,且抗肿瘤作用机制尚未阐明。针对这些问题,本研究首先以聚己内酯[poly(caprolactone),PCL]和聚乙二醇-聚ε-己内酯[poly(ethylene glycol)-co-poly(ε-caprolactone),PEG-PCL]为载体材料,通过纳米沉淀法制备了包载CY-1-4的纳米粒(CY-1-4 NPs)以改进其溶解性,测定CY-1-4 NPs对B16-F10细胞活性氧(reactive oxygen species,ROS)水平的影响、脂质活性氧抑制剂ferrostatin-1和铁螯合剂去铁胺(deferoxamine,DFO)对CY-1-4 NPs诱导B16-F10细胞死亡的修复作用及原卟啉(protoporphyrin IX,PPIX)对CY-1-4 NPs诱导B16-F10细胞死亡的促进作用,研究了CY-1-4 NPs诱导B16-F10的细胞毒是否存在铁死亡途径。结果表明,纳米化策略可明显改善CY-1-4的水溶性,所得纳米粒粒径约为116 nm,包封率约为83%,载药量约为4.80%。铁死亡机制验证结果表明,CY-1-4 NPs可以明显提高B16-F10细胞内ROS水平,ferrostatin-1和DFO可以一定程度抑制CY-1-4 NPs对B16-F10细胞的细胞毒作用,而PPIX可以促进CY-1-4 NPs对B16-F10细胞的细胞毒。上述结果均证明铁死亡是纳米化色胺酮类化合物CY-1-4诱导细胞死亡的机制之一。
关键词:    色胺酮类化合物CY-1-4      纳米粒      黑色素瘤      死亡机制      铁死亡     
Tryptanthrin derivative CY-1-4 nanoparticle induces ferroptosis in B16-F10 cells
YANG Can-yu1, WANG Da-kuan1, DENG Hai-liang1, ZHANG Hua1, DAI Wen-bing1, HE Bing1, ZHANG Qiang1,2, MENG Xiang-bao2, WANG Xue-qing1
1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Peking University, Beijing 100191, China;
2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Abstract:
CY-1-4 is a tryptanthrin derivative exhibiting antitumor activity. The solubility of CY-1-4 was poor and the corresponding mechanism needs further study. To solve this problem, we prepared nanoparticles encapsulated with CY-1-4 (CY-1-4 NPs) by nanoprecipitation method using poly(caprolactone) (PCL) and poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) as carriers to improve solubility. We then explored whether CY-1-4 NPs induced B16-F10 cytotoxicity via ferroptosis by determining the effect of CY-1-4 NPs on reactive oxygen (ROS) levels, repairing efficacy of lipid reactive oxygen inhibitor ferrostatin-1 and iron chelator deferoxamine (DFO), and potentiation of protoporphyrin (PPIX) induced B16-F10 cell death. The results showed that nanoparticlated strategy significantly improved solubility of CY-1-4. With the particle size about 116 nm, encapsulating efficacy was about 83% and the drug loading capacity was about 4.80%. Ferroptosis mechanistic studies indicated that CY-1-4 NPs could improve the ROS level in B16-F10 cells, whereas ferrostatin-1 and DFO could partly inhibited the cytotoxicity and PPIX could potentiated the cytotoxicity of CY-1-4 NPs in B16-F10 cells. These results showed that ferroptosis was one of the cell death mechanisms induced by tryptanthrin derivative CY-1-4 nanoparticle.
Key words:    tryptanthrin derivative CY-1-4    nanoparticle    melanoma    cell death mechanism    ferroptosis   
收稿日期: 2019-03-22
DOI: 10.16438/j.0513-4870.2019-0200
基金项目: 国家自然科学基金资助项目(31671017,81872809).
通讯作者: 王学清,Tel:86-10-82805935,E-mail:wangxq@bimu.edu.cn
Email: wangxq@bimu.edu.cn
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参考文献:
[1] Pitzer KK, Scovill JP, Kyle DE, et al. Indolo 2, 1-B quinazole-6, 12-dione antimalarial compounds and methods of treating malaria therewith:US, EP1032574[P]. 1999-09-28.
[2] Hicks RP, Nichols DA, Ditusa CA, et al. Evaluation of 4-azaindolo[2,1-b]quinazoline-6, 12-diones' interaction with hemin and hemozoin:a spectroscopic, X-ray crystallographic and molecular modeling study[J]. Int Electr J Mol Design, 2005, 4:751-764.
[3] Kimoto T, Hino K, Koya-Miyata S, et al. Cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (U-937 and Hl-60) by tryptanthrin, an active ingredient of Polygonum Tinctorium Lour[J]. Pathol Int, 2001, 51:315-325.
[4] Jun KY, Park SE, Liang JL, et al. Benzo[b]tryptanthrin inhibits MDR1, topoisomerase activity, and reverses adriamycin resistance in breast cancer cells[J]. ChemMedChem, 2015, 10:827-835.
[5] Yang SS, Li XS, Hu FF, et al. Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2, 3-dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice[J]. J Med Chem, 2013, 56:8321-8331.
[6] Hwang JM, Oh T, Kaneko T, et al. Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents[J]. J Nat Prod, 2013, 76:354-367.
[7] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149:1060-1072.
[8] Xie Y, Hou W, Song X, et al. Ferroptosis:process and function[J]. Cell Death Differ, 2016, 23:369-379.
[9] Meng XB, Chen Y, Li ZJ, et al. Nitrogen heterocyclic tryptamine ketone derivative and application as IDO1 and/or TDO inhibitor:WO, WO2017173973A1[P]. 2017-10-12.
[10] Ou WJ, Mulik RS, Anwar A, et al. Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma[J]. Free Radic Biol Med, 2017, 112:597-607.
[11] Zhang SM, Gerhard GS. Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target[J]. PLoS One, 2009, 4:e7472.
[12] Yang SS, Du LS, Ri HN, et al. Screening of tryptanthrin derivatives of indoleamine 2, 3-dioxygenase (IDO) inhibitor and their antitumor activity in vitro[J]. Fudan Univ J Med Sci (复旦学报(医学版)), 2014, 41:149-155.
[13] Dolma S, Lessnick SL, Hahn WC, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3:285-296.
[14] Zhao Z, Bao XQ, Zhang D. Mechanisms of ferroptosis and its involvement in Parkinson's disease[J]. Acta Pharm Sin (药学学报), 2019, 54:399-406.
[15] Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15:234-245.
[16] Yagoda N, von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels[J]. Nature, 2007, 447:864-868.
[17] Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis[J]. eLife, 2014, 3:e02523.
[18] Barradas MA, Jeremy JY, Kontoghiorghes GJ, et al. Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity[J]. FEBS Lett, 1989, 245:105-109.
[19] Zhou WB, Kong CF, Qin GW, et al. Research progresss on mechanism of ferroptosis[J]. Prog Biochem Biophys (生物化学与生物物理进展), 2018, 45:16-22.
[20] Eling N, Reuter L, Hazin J, et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells[J]. Oncoscience, 2015, 2:517-532.
[21] Lin RY, Zhang ZH, Chen LF, et al. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells[J]. Cancer Lett, 2016, 381:165-175.
[22] Huang XJ, Ma ZQ, Zhang WP, et al. Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1α activation in C6 glioma cells[J]. J Pharm Pharmacol, 2010, 59:849-856.
[23] Disbrow GL, Baege AC, Kierpiec KA, et al. Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo[J]. Cancer Res, 2005, 65:10854-10861.
[24] Yan DJ, Lin YW, Tan XS. Heme-containing enzymes and inhibitors for tryptophan metabolism[J]. Metallomics, 2017, 9:1230-1240.