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类姜黄素提取自高良姜和日本桤木,它在胰腺癌细胞株中可以抑制FoxM1信号传导

 

           高良姜隶属于姜科植物,起源于中国,现在整个东南亚都有栽培(图1所示)。高良姜的根茎其药用价值很高,也可用于烹饪及制作香料。日本桤木或东亚赤杨木分布在日本,韩国,中国华东以及俄罗斯地区。二芳基庚烷类化合物可从此类药用植物中提炼出来,它是姜黄素抗癌剂的一种成分。二芳基庚烷类化合物可以抑制PANC-1(如KRAS和G12D杂合体,TP53,P72R和273RH纯合体)胰腺癌细胞株[1,2]的成长。其机理是它可以抑制FoxM1转录因子的信号传导。

 

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图1:高良姜 参考文献:Biodiversity Heritage Library

此照片未经修改,知识共享:Attribution 2.0 Generic (CC BY 2.0).

 

        FoxM1是胰腺癌[3]中枢重要的转录因子。它能促进基因转录,主要参与细胞周期进程以及细胞存活,迁移和侵袭[4]。FoxM1转录已经被证明音猬因子对结肠直肠癌有积极作用。Dong等人建议,由于Gli1/2蛋白质下调,作为对于二芳基庚烷类化合物的反应,FoxM1靶基因也会被相应下调。有趣的是,Stat3 信号传导被发现可以被如HO-3867等其它二芳基庚烷类化合物下调,并且,Stat3 信号传导可以间接地被Gli1通过IL-6上调。不同二芳基庚烷类化合物在胰腺癌中能够抑制FoxM1和Stat3信号传导的程度仍是一个开放的问题。

 

参考文献:

  1. Dong GZ, Jeong JH, Lee YI, Lee SY, Zhao HY, Jeon R, Lee HJ, Ryu JH. Diarylheptanoids suppress proliferation of pancreatic cancer PANC-1 cells through modulating shh-Gli-FoxM1 pathway. Arch Pharm Res. 2017 Apr;40(4):509-517. Doi: 10.1007/s12272-017-0905-2. PubMed PMID: 28258481.
  2. Gradiz R, Silva HC, Carvalho L, Botelho MF, Mota-Pinto A. MIA PaCa-2 and PANC-1 – pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 2016 Feb 17;6:21648. Doi: 10.1038/srep21648. PubMed PMID: 26884312.
  3. Akbari B, Mohammadnia A, Yaqubi M, Wee P, Mahdiuni H. Comprehensive Dissection of Transcriptome Data and Regulatory Factors in Pancreatic Cancer Cells. J Cell Biochem. 2017 Apr 12. doi: 10.1002/jcb.26053. PubMed PMID: 28401644.
  4. Quan M, Wang P, Cui J, Gao Y, Xie K. The roles of FOXM1 in pancreatic stem cells and carcinogenesis. Mol Cancer. 2013 Dec 10;12:159. Doi: 10.1186/1476-4598-12-159. Review. PubMed PMID: 24325450.
  5. Wang D, Hu G, Du Y, Zhang C, Lu Q, Lv N, Luo S. Aberrant activation of hedgehog signaling promotes cell proliferation via the transcriptional activation of forkhead Box M1 in colorectal cancer cells. J Exp Clin Cancer Res. 2017 Feb 2;36(1):23. doi: 10.1186/s13046-017-0491-7. PubMed PMID: 28148279.
  6. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008 Sep 26;321(5897):1801-6. Doi: 10.1126/science.1164368. PubMed PMID: 18772397.
  7. Hu Y, Zhao C, Zheng H, Lu K, Shi D, Liu Z, Dai X, Zhang Y, Zhang X, Hu W, Liang G. A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs. 2017 Apr;28(4):392-400. Doi: 10.1097/CAD.0000000000000470. PubMed PMID: 28067673.
  8. Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL, Couch F, Wetmore C, Pasca di Magliano M, Fernandez-Zapico ME. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013 Apr 26;288(17):11786-94. doi: 10.1074/jbc.M112.438846. PubMed PMID:23482563.

 

牡丹酚是与免疫治疗剂协同作用的具有潜力的抗癌剂

 

       牡丹酚, 1-(2-羟基-4-甲氧基苯基) 乙酮 (图1)是一种通常在牡丹 (丹皮), 天南星和日本薯蓣中含有的酚类化合物. 它是一些中药[1]的重要组成成分。

 

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图 1: 牡丹酚, 1-(2-羟基-4-甲氧基苯基) 乙酮.

 

       牡丹酚已经被证明可以在卵巢癌,胃癌, 结肠直肠癌, 食管癌 , 肝癌, 乳腺癌 , 黑色素瘤, 前列腺癌 和 肺癌 [2, 3, 4, 5, 6, 7, 8, 9, 10]中诱发癌细胞凋亡。

       牡丹酚具有抗炎和抗纤维化的作用. 在CW-2 大肠癌细胞传导中,牡丹酚可抑制肿瘤坏死因子α (TNFα),从而降低诱导NF-κB以及诱导STAT1 [11]的干扰素(IFNγ)的转录活性。它也可能对STAT3 [3]具有抑制作用。在结肠直肠癌细胞中,牡丹酚也可增加RUNX3的表达能级。RUNX3在上皮间质转化(EMT)的纤维化促进过程中具有复杂的作用,但至少在某些情况下,RUNX3 可预防 EMT [12, 13],而耐药性和免疫抑制都与EMT相关。

 

       最重要地是,牡丹酚可有效缓解耐药性。它可以增强顺铂[14],阿霉素[15]和紫杉醇[16]的功效。除了抗纤维化作用之外,可通过抑制AKT信号转导通路来调解这些影响。

 

                   已知通过减少环氧合酶(COX-2)的表达,可以降低其代谢产物前列腺素E2(PGE2) [18]的水平,牡丹酚在免疫治疗抗肿瘤的免疫抑制微环境中应用广泛。已知PGE2在抑制CD4和CD8 T细胞[19]的肿瘤微环境中可促进髓源性抑制细胞再生。牡丹酚可与新型癌症免疫治疗剂协同作用。

 

参考文献:

  1. Deng C, Yao N, Wang B, Zhang X. Development of microwave-assisted extraction followed by headspace single-drop microextraction for fast determination of paeonol in traditional Chinese medicines. J Chromatogr A. 2006 Jan 20;1103(1):15-21. PubMed PMID: 16309693.
  2. Xu Y, Zhu JY, Lei ZM, Wan LJ, Zhu XW, Ye F, Tong YY. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem. 2016 Nov 10. PubMed PMID: 27834040.
  3. Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways. IUBMB Life. 2015 Oct;67(10):778-88. doi: 10.1002/iub.1435. PubMed PMID: 26452780.
  4. Ou Y, Li Q, Wang J, Li K, Zhou S. Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma. Biomol Ther (Seoul). 2014 Jul;22(4):341-6. doi: 10.4062/biomolther.2013.106. PubMed PMID: 25143814.
  5. Lei Y, Li HX, Jin WS, Peng WR, Zhang CJ, Bu LJ, Du YY, Ma T, Sun GP. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol. 2013 Dec;89(12):1079-86. doi: 10.3109/09553002.2013.825058. PubMed PMID: 23875954.
  6. Yin J, Wu N, Zeng F, Cheng C, Kang K, Yang H. Paeonol induces apoptosis in human ovarian cancer cells. Acta Histochem. 2013 Oct;115(8):835-9. Doi: 10.1016/j.acthis.2013.04.004. PubMed PMID: 23768958.
  7. Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H. Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol. 2010 Sep 21;16(35):4483-90. PubMed PMID: 20845518.
  8. Xing G, Zhang Z, Liu J, Hu H, Sugiura N. Antitumor effect of extracts from moutan cortex on DLD-1 human colon cancer cells in vitro. Mol Med Rep. 2010 Jan-Feb;3(1):57-61. doi: 10.3892/mmr_00000218. PubMed PMID: 21472200.
  9. Sun GP, Wan X, Xu SP, Wang H, Liu SH, Wang ZG. Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus. 2008;21(8):723-9. doi: 10.1111/j.1442-2050.2008.00840.x. PubMed PMID: 18522637.
  10. Chunhu Z, Suiyu H, Meiqun C, Guilin X, Yunhui L. Antiproliferative and apoptotic effects of paeonol on human hepatocellular carcinoma cells. Anticancer Drugs. 2008 Apr;19(4):401-9. doi: 10.1097/CAD.0b013e3282f7f4eb. PubMed PMID: 18454050.
  11. Ishiguro K, Ando T, Maeda O, Hasegawa M, Kadomatsu K, Ohmiya N, Niwa Y, Xavier R, Goto H. Paeonol attenuates TNBS-induced colitis by inhibiting NF-kappaB and STAT1 transactivation. Toxicol Appl Pharmacol. 2006 Nov 15;217(1):35-42. PubMed PMID: 16928387.
  12. Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, Wood LD, Goggins M, Hruban RH, Chang AE, Calses P, Thorsen SM, Hingorani SR. RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. Cell. 2015 Jun 4;161(6):1345-60. doi: 10.1016/j.cell.2015.04.048. PubMed PMID: 26004068.
  13. Voon DC, Wang H, Koo JK, Nguyen TA, Hor YT, Chu YS, Ito K, Fukamachi H, Chan SL, Thiery JP, Ito Y. Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. Stem Cells. 2012 Oct;30(10):2088-99. doi: 10.1002/stem.1183. PubMed PMID: 22899304.
  14. Xu SP, Sun GP, Shen YX, Peng WR, Wang H, Wei W. Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines. Acta Pharmacol Sin. 2007 Jun;28(6):869-78. PubMed PMID: 17506946.
  15. Fan L, Song B, Sun G, Ma T, Zhong F, Wei W. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells. PLoS One. 2013 May 3;8(5):e62627. Doi: 10.1371/journal.pone.0062627. PubMed PMID: 23658755.
  16. Cai J, Chen S, Zhang W, Hu S, Lu J, Xing J, Dong Y. Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2. Phytomedicine. 2014 Jun 15;21(7):984-91. doi: 10.1016/j.phymed.2014.02.012. PubMed PMID: 24680370.
  17. Zhang W, Cai J, Chen S, Zheng X, Hu S, Dong W, Lu J, Xing J, Dong Y. Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway. Mol Med Rep. 2015 Jul;12(1):1506-14. doi: 10.3892/mmr.2015.3468. PubMed PMID: 25760096.
  18. Li M, Tan SY, Wang XF. Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE₂ synthesis and COX-2 expression. Oncol Rep. 2014 Dec;32(6):2845-53. doi: 10.3892/or.2014.3543. PubMed PMID: 25322760.
  19. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007 May 1;67(9):4507-13. PubMed PMID: 17483367.

 

治疗癌症的三种溶瘤病毒药物

 

  溶瘤病毒药物(基于病毒触发癌细胞死亡和激发免疫反应的药物)是早已获准上市的基因治疗药物。

           早在2003年,今又生被中国国家食品药品监督管理局(SFDA)批准用于治疗头颈部鳞状细胞癌(HNSCC) [1]。它是由具有复制缺陷的5型腺病毒基因和人类野生型P53肿瘤抑制基因重组而成。今又生因其复制缺陷并不能称为“真正”的溶瘤病毒,把它放在这里介绍,是因为近年来发现溶瘤病毒疗法会激发对肿瘤的免疫反应。这可能会导致间接肿瘤裂解,并且比直接病毒裂解更重要。事实上,今又生确实会导致肿瘤细胞裂解。

         2005年,中国SFDA批准了重组人5型腺病毒药物,称为安柯瑞[2]。安柯瑞是删除人5型腺病毒E1B和E3区部分基因片段而获得的一种溶瘤性腺病毒。因为资金原因,在美国研发的一种类似病毒,名为肿瘤增殖病毒项目在III期临床试验阶段不得不被迫停止,此次资金问题导致美国溶瘤病毒技术发展滞后中国十年。

        在2015年10月,美国食品药品监督管理局(FDA)批准Imlygic上市,它主要用于治疗不能经手术完全切除的黑色素瘤病灶[3]。在2016年1月,欧洲也批准Imlygic上市,用于治疗一些不能进行手术的黑色素瘤[4]。Imlygic是一种单纯疱疹病毒1(HSV-1),通过注射基于溶瘤细胞载体传输,Imlygic是从单纯疱疹病毒1(JS1)中新鲜分离出来的,并释放粒细胞-巨噬细胞集落刺激因子(GM-CSF),GM-CSF替代双拷贝ICP34.5基因,并传输溶瘤细胞载体进入肿瘤细胞中。

        FDA批准的第一个项目已经过去一段时间了,到现在有很多的溶瘤病毒已经在临床试验中获得了更多的批准。

参考文献:

 

  1. Pearson, Sue, Hepeng Jia, and Keiko Kandachi. ‘China Approves First Gene Therapy’. Nature Biotechnology 22, no. 1 (January 2004): 3–4. doi:10.1038/nbt0104-3.
  2. Garber, Ken. ‘China Approves World’s First Oncolytic Virus Therapy For Cancer Treatment’. Journal of the National Cancer Institute 98, no. 5 (3 January 2006): 298–300. doi:10.1093/jnci/djj111.
  3. ‘FDA Approves Amgen’s Injected Immunotherapy for Melanoma’. Reuters, 27 October 2015. http://www.reuters.com/article/us-amgen-fda-idUSKCN0SL2YH20151027.
  4. Semedo, Daniela, and PhD. ‘Metastatic Melanoma Therapy, Imlygic, Now Available in EU’. Immuno-Oncology News, 7 January 2016. http://immuno-oncologynews.com/2016/01/07/metastatic-melanoma-therapy-imlygic-now-available-eu/.
  5. Liu BL, Robinson M, Han Z-Q, Branston RH, English C, Reay P, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther 2003; 10:292–303. [PMID: 12595888]

 

KRAS突变疫苗用于胰腺癌的临床发展

 

        最近一份病例报告显示,采用T细胞转移靶向KRAS G12D突变治疗转移性结直肠癌患者诱导了肿瘤消退[1]。临床试验结果显示T细胞能够靶向消灭表达KRAS G12D突变肽的结肠肿瘤细胞,并在其细胞表面完成与主要组织相容性复合体(MHC)I蛋白的结合。它对所有的癌症都有影响,具有普遍的突变KRAS表达。在最常见的胰腺癌中,KRAS在90%的病例中发生突变。

 

        Targovax公司和GlobeImmune公司正在开发KRAS突变肽的疫苗,用于治疗胰腺癌患者。这些疫苗涉及注射肽和在体内生成T细胞对胰腺癌的反应。Targovax公司的RAS疫苗名为TG01。该公司报告显示, I / II期的第一阶段中使用TG01和吉西他滨药物对切除胰腺癌[2]患者的试验表明,在92%的患者中TG01会诱导免疫反应。中期存活率数据显示,15名可评估患者中有14名在一年之后仍然存活。充分证明了TG01的安全性和耐受性。

 

        在第二阶段的临床试验中(see here),GlobeImmune的产品在胰腺癌患者临床试验中表现出更高的功效。根据肿瘤蛋白表达谱,已开发出一种用于预测胰腺癌患者最有可能从该疫苗中获益的MALDI-TOF质谱诊断。

 

               正如GlobeImmune公司的第二阶段试验所证明的那样,并不是所有患有KRAS突变的胰腺癌患者都能受益。这很可能是因为胰腺癌的“冷”immunoscore (see here)。KRAS疫苗与提高胰腺癌immunoscore的药物组合策略可能会增加对突变RAS疫苗反应的患者数量。

 

参考文献:

 

  1. Tran E, Robbins PF, Lu Y-C, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255-2262. DOI: 10.1056/NEJMoa1609279.
  2. ClinicalTrials.gov Identifier: NCT02261714 – Antigen-specific Cancer Immunotherapy (TG01) and Gemcitabine as Adjuvant Therapy in Resected Pancreatic Cancer.
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