垫状卷柏提取物诱导凋亡抗肿瘤作用研究

樊炼; 吴永平; 瞿慧; 吴信华; 曹园

垫状卷柏提取物诱导凋亡抗肿瘤作用研究

樊炼¹,
吴永平²,
瞿慧¹,
吴信华^1,3,
曹园¹

1.
南京中医药大学附属医院/江苏省中医院，江苏南京 210029
2.
江苏省药物研究所药化室，江苏南京 210009
3.
南京中医药大学药学院，江苏南京 210023

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- 刊出日期: 2019-11-09

Selaginella Pulvinata<\i> Extract Exerts Antitumor Efficacy in H22 Tumor-Bearing Mice via Induction of Apoptosis

FANLian¹,

WUYong-ping²,

QUHui¹,

WUXin-hua^1,3,

CAOYuan¹

1.
Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China

2.
Department of Medical Chemistry, Jiangsu Provincial Institute of Materia Medica, Nanjing, 210009, China

3.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

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摘要: 目的研究垫状卷柏提取物抗肿瘤作用及相关机制。方法采用皮下接种H22肝癌细胞株构建小鼠H22肝癌移植瘤模型，随机分为对照组（生理盐水）、5-FU组（30 mg/kg）、垫状卷柏提取物（SP）高、低剂量组（189、63 mg/kg），连续灌胃15 d。观察小鼠肿瘤生长情况，计算抑瘤率及肝、脾、胸腺指数；TUNEL法观察肿瘤组织细胞凋亡，Western blot测定凋亡相关蛋白的表达，qPCR检测Bax mRNA和Bcl-2 mRNA。结果与对照组比较，SP高、低剂量组小鼠体质量及肝、脾、胸腺指数均无显著差异；SP高、低剂量组小鼠的肿瘤质量均显著降低，呈现较高抑瘤率（P<0.01），且高剂量组与5-FU组相近；经TUNEL染色法观察，可见明显凋亡形态改变。qPCR检测表明，SP显著上调Bax mRNA的表达，下调Bcl-2 mRNA的表达。Western blot结果显示SP处理后，Bax、cytochrome c及cleaved caspase-3，caspase-8和caspase-9的表达显著上调（P<0.01），Bcl-2表达明显减弱，呈剂量依赖性。结论 SP有效抑制H22小鼠体内肿瘤生长，其机制与激活caspase诱导凋亡相关。

关键词:
垫状卷柏提取物 /

抗肿瘤 /

肝细胞癌 /

凋亡

Abstract: OBJECTIVE To investigate the in vivo antitumor effect of S. pulvinata extract (SP) and its underlying mechanisms. METHODS A solid tumor H22-transplanted model in mice was established and randomly divided into normal saline control group， 5-FU chemotherapy group (30 mg/kg)， low-dose SP group (63 mg/kg)， and high-dose SP group (189 mg/kg). All mice received respective treatment once daily for 15 days. The tumor weights were monitored， and the inhibition rates as well as organ indexes were calculated. The potential mechanism was investigated using TUNEL staining， qPCR and Western blot analysis. RESULTS Compared with the control group， SP significantly inhibited tumor growth without producing obvious side-effects on body weight and immune organs. Observations from a TUNEL staining experiment demonstrated that SP noticeably induced apoptosis in tumor tissues. Moreover， qPCR showed that SP upregulated the mRNA levels of Bax and downregulated those of Bcl-2， resulting in the release of cytochrome c， which is in agreement with their protein expressions. Further Western blot analysis revealed that SP significantly activated and induced the cleavage of caspase-3， caspase-8 and caspase-9. CONCLUSION The findings clearly demonstrates that the mechanism of SP involves the induction of apoptosis. The study suggests that SP possesses potent in vivo antitumor effects against HCC.

Keywords:
Selaginella pulvinata<\i> extract /

antitumor /

hepatocellular carcinoma /

apoptosis

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参考文献(27)

[1] SIEGEL R， MILLER K， JEMAL A. Cancer statistics [J]. CA Cancer J Clin， 2017， 67(1): 7-30.

[2] VENOOK A， PAPANDREOU C， FURUSE J， et al. The Incidence and epidemiology of hepatocellular carcinoma: A global and regional perspective [J]. Oncologist， 2010， 15(S4): 5-13.

[3] Editorial Board of "Zhong Hua Ben Cao"， State Administration of Traditional Chinese Medicine of the People's Republic of China. Zhong Hua Ben Cao (Vol 4) [M]. Shanghai: Shanghai Scientific and Technical Publishers， 1999: 387.

[4] CAO Y， CHEN JJ， TAN NH， et al. Antimicrobial selaginellin derivatives from Selaginella pulvinata<\i> [J]. Bioorg Med Chem Lett， 2010， 20(8): 2456-2460.

[5] CAO Y， CHEN JJ， TAN NH， et al. Structure determination of selaginellins G and H from Selaginella pulvinata<\i> by NMR spectroscopy [J]. Magn Reson Chem， 2010， 48(8): 656-659.

[6] CAO Y， YAO Y， HUANG XJ， et al. Four new selaginellin derivatives from Selaginella pulvinata<\i>: Mechanism of racemization process in selaginellins with quinone methide [J]. Tetrahedron， 2015， 71(10): 1581-1587.

[7] CAO Y， ZHAO M， ZHU Y， et al. Diselaginellin B， an unusual dimeric molecule from Selaginella pulvinata<\i>， inhibited metastasis and induced apoptosis of SMMC-7721 human hepatocellular carcinoma cells [J]. J Nat Prod， 2017， 80(12): 3151-3158.

[8] CAO Y， WU YP， ZHOU XW， et al. Simultaneous determination of selaginellins and biflavones in Selaginella tamariscina<\i> and Selaginella pulvinata<\i> by HPLC-DAD [J]. China J Chin Mater Med， 2012， 37(9): 1254-1258.

[9] LEE IS， NISHIKAWA A， FURUKAWA F， et al. Effects of Selaginella tamariscina<\i> on in vitro<\i> tumor cell growth， p53 expression， G1 arrest and in vivo<\i> gastric cell proliferation [J]. Cancer Lett， 1999， 144(1): 93-99.

[10] YANG JS， LIN CW， HSIN CH， et al. Selaginella tamariscina<\i> attenuates metastasis via Akt pathways in oral cancer cells [J]. PLoS ONE， 2013， 8(6): e68035.

[11] YANG SF， CHU SC， LIU SJ， et al. Antimetastatic activities of Selaginella tamariscina<\i> (Beauv.) on lung cancer cells in vitro <\i>and in vivo<\i> [J]. J Ethnopharmacol， 2007， 110(3): 483-489.

[12] HSIN CH， WU BC， CHUANG CY， et al. Selaginella tamariscina<\i> extract suppresses TPA-induced invasion and metastasis through inhibition of MMP-9 in human nasopharyngeal carcinoma HONE-1 cells [J]. BMC Complement Altern Med， 2013， 13: 234.

[13] LEE S， KIM H， KANG JW， et al. The biflavonoid amentoflavone induces apoptosis via suppressing E7 expression， cell cycle arrest at sub-G₁ phase， and mitochondria-emanated intrinsic pathways in human cervical cancer cells [J]. J Med Food， 2011， 14(14): 808-816.

[14] PEI JS， LIU CC， HSU YN， et al. Amentoflavone induces cell-cycle arrest and apoptosis in MCF-7 human breast cancer cells via mitochondria-dependent pathway [J]. In Vivo， 2012， 26(6): 963-970.

[15] GURUVAYOORAPPAN C，KUTTAN G. Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2， MMP-9， prolyl hydroxylase， lysyl oxidase， VEGF， ERK-1， ERK-2， STAT-1， nm23 and cytokines in lung tissues of C57BL/6 mice [J]. Immunopharmacol Immunotoxicol， 2008， 30(4): 711-727.

[16] GURUVAYOORAPPAN C， KUTTAN G. Inhibition of tumor specific angiogenesis by amentoflavone [J]. Biochemistry， 2008， 73(73): 209-218.

[17] LEE JS， LEE MS， OH WK， et al. Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breast cancer cells [J]. Biol Pharm Bull， 2009， 32(8): 1427-1432.

[18] LEE JS， SUL JY， PARK JB， et al. Fatty acid synthase inhibition by amentoflavone suppresses HER2/neu (erbB2) oncogene in SKBR3 human breast cancer cells [J]. Phytother Res， 2013， 27(5): 713-720.

[19] KUHAJDA FP. Fatty acid synthase and cancer: New application of an old pathway [J]. Cancer Res， 2006， 66(12): 5977-5980.

[20] PANDEY PR， LIU W， XING F， et al. Anti-cancer drugs targeting fatty acid synthase (FAS) [J]. Recent Pat Anticancer Drug Discov， 2012， 7(2): 185-197.

[21] BOSISIO E， SAPONARA R. Inhibition of cAMP-Phosphodiesterase by biflavones of Ginkgo biloba <\i>in rat adipose tissue [J]. J Nat Prod， 1998， 61(11): 1386-1387.

[22] SHIM SY， LEE S， LEE M. Biflavonoids isolated from Selaginella tamariscina<\i> and their anti-inflammatory activities via ERK 1/2 signaling [J]. Molecules， 2018， 23: 926.

[23] SILVA GL， CHAI H， GUPTA MP， et al. Cytotoxic biflavonoids from Selaginella willdenowii<\i> [J]. Phytochemistry， 1995， 40(1): 129-134.

[24] ZHANG GG， JING Y， ZHANG HM， et al. Isolation and cytotoxic activity of selaginellin derivatives and biflavonoids from Selaginella tamariscina<\i> [J]. Planta Med， 2012， 78(4): 390-392.

[25] YANG C， SHAO YT， LI K， et al. Bioactive selaginellins from Selaginella tamariscina <\i>(Beauv.) Spring [J]. Beilstein J Org Chem， 2012， 8(1): 1884-1889.

[26] HANAHAN D， WEINBERG RA. Hallmarks of cancer: the next generation [J]. Cell， 2011， 144(5): 646-674.

[27] PORTT L， NORMAN G， CLAPP C， et al. Anti-apoptosis and cell survival: A review [J]. Biochim Biophys Acta， 2011， 1813(1): 238-259.

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1. 肖国素，余洲，陈丽娜，吴玉婷，曹珊，张蕾，黄妮雯. 卷柏总黄酮通过调节Nrf2/HO-1信号通路减轻机械通气相关性肺损伤的机制. 西部医学. 2025(01): 5-9 . 百度学术

2. 吕雪峰，王莲萍，张明天，张莲珠，SONG Yu. 卷柏总黄酮的纯化工艺与细胞保护作用. 海南热带海洋学院学报. 2024(02): 104-112 . 百度学术

3. 孙允红，王晓晴，赵方舒，倪雯婷，尹怡铭，李保宏，侯林. 垫状卷柏的化学成分、药理作用现代研究及质量标志物(Q-marker)的预测分析. 中药药理与临床. 2023(11): 115-121 . 百度学术

4. 张莲珠，刘君，李驰坤，张雅剑，宋宇，成光宇. 卷柏总黄酮研究进展. 中国医药. 2022(03): 472-476 . 百度学术

5. 张应. 垫状卷柏提取物对体外肿瘤细胞生长抑制作用的研究. 中国校医. 2022(10): 785-787 . 百度学术

6. 吕华伟，李宇霞，罗蒙，江恒沛，张宏建，颜继忠. 垫状卷柏化学成分的研究. 中成药. 2021(01): 102-105 . 百度学术

7. 张应. 垫状卷柏提取物对人白血病细胞K562诱导凋亡的研究. 中国疗养医学. 2021(09): 913-914 . 百度学术

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文章访问数: 710

HTML全文浏览量: 8

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被引次数: 11

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刊出日期: 2019-11-09

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摘要
HTML全文
参考文献(27)
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[1]	SIEGEL R， MILLER K， JEMAL A. Cancer statistics [J]. CA Cancer J Clin， 2017， 67(1): 7-30.
[2]	VENOOK A， PAPANDREOU C， FURUSE J， et al. The Incidence and epidemiology of hepatocellular carcinoma: A global and regional perspective [J]. Oncologist， 2010， 15(S4): 5-13.
[3]	Editorial Board of "Zhong Hua Ben Cao"， State Administration of Traditional Chinese Medicine of the People's Republic of China. Zhong Hua Ben Cao (Vol 4) [M]. Shanghai: Shanghai Scientific and Technical Publishers， 1999: 387.
[4]	CAO Y， CHEN JJ， TAN NH， et al. Antimicrobial selaginellin derivatives from Selaginella pulvinata<\i> [J]. Bioorg Med Chem Lett， 2010， 20(8): 2456-2460.
[5]	CAO Y， CHEN JJ， TAN NH， et al. Structure determination of selaginellins G and H from Selaginella pulvinata<\i> by NMR spectroscopy [J]. Magn Reson Chem， 2010， 48(8): 656-659.
[6]	CAO Y， YAO Y， HUANG XJ， et al. Four new selaginellin derivatives from Selaginella pulvinata<\i>: Mechanism of racemization process in selaginellins with quinone methide [J]. Tetrahedron， 2015， 71(10): 1581-1587.
[7]	CAO Y， ZHAO M， ZHU Y， et al. Diselaginellin B， an unusual dimeric molecule from Selaginella pulvinata<\i>， inhibited metastasis and induced apoptosis of SMMC-7721 human hepatocellular carcinoma cells [J]. J Nat Prod， 2017， 80(12): 3151-3158.
[8]	CAO Y， WU YP， ZHOU XW， et al. Simultaneous determination of selaginellins and biflavones in Selaginella tamariscina<\i> and Selaginella pulvinata<\i> by HPLC-DAD [J]. China J Chin Mater Med， 2012， 37(9): 1254-1258.
[9]	LEE IS， NISHIKAWA A， FURUKAWA F， et al. Effects of Selaginella tamariscina<\i> on in vitro<\i> tumor cell growth， p53 expression， G1 arrest and in vivo<\i> gastric cell proliferation [J]. Cancer Lett， 1999， 144(1): 93-99.
[10]	YANG JS， LIN CW， HSIN CH， et al. Selaginella tamariscina<\i> attenuates metastasis via Akt pathways in oral cancer cells [J]. PLoS ONE， 2013， 8(6): e68035.
[11]	YANG SF， CHU SC， LIU SJ， et al. Antimetastatic activities of Selaginella tamariscina<\i> (Beauv.) on lung cancer cells in vitro <\i>and in vivo<\i> [J]. J Ethnopharmacol， 2007， 110(3): 483-489.
[12]	HSIN CH， WU BC， CHUANG CY， et al. Selaginella tamariscina<\i> extract suppresses TPA-induced invasion and metastasis through inhibition of MMP-9 in human nasopharyngeal carcinoma HONE-1 cells [J]. BMC Complement Altern Med， 2013， 13: 234.
[13]	LEE S， KIM H， KANG JW， et al. The biflavonoid amentoflavone induces apoptosis via suppressing E7 expression， cell cycle arrest at sub-G₁ phase， and mitochondria-emanated intrinsic pathways in human cervical cancer cells [J]. J Med Food， 2011， 14(14): 808-816.
[14]	PEI JS， LIU CC， HSU YN， et al. Amentoflavone induces cell-cycle arrest and apoptosis in MCF-7 human breast cancer cells via mitochondria-dependent pathway [J]. In Vivo， 2012， 26(6): 963-970.
[15]	GURUVAYOORAPPAN C，KUTTAN G. Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2， MMP-9， prolyl hydroxylase， lysyl oxidase， VEGF， ERK-1， ERK-2， STAT-1， nm23 and cytokines in lung tissues of C57BL/6 mice [J]. Immunopharmacol Immunotoxicol， 2008， 30(4): 711-727.
[16]	GURUVAYOORAPPAN C， KUTTAN G. Inhibition of tumor specific angiogenesis by amentoflavone [J]. Biochemistry， 2008， 73(73): 209-218.
[17]	LEE JS， LEE MS， OH WK， et al. Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breast cancer cells [J]. Biol Pharm Bull， 2009， 32(8): 1427-1432.
[18]	LEE JS， SUL JY， PARK JB， et al. Fatty acid synthase inhibition by amentoflavone suppresses HER2/neu (erbB2) oncogene in SKBR3 human breast cancer cells [J]. Phytother Res， 2013， 27(5): 713-720.
[19]	KUHAJDA FP. Fatty acid synthase and cancer: New application of an old pathway [J]. Cancer Res， 2006， 66(12): 5977-5980.
[20]	PANDEY PR， LIU W， XING F， et al. Anti-cancer drugs targeting fatty acid synthase (FAS) [J]. Recent Pat Anticancer Drug Discov， 2012， 7(2): 185-197.
[21]	BOSISIO E， SAPONARA R. Inhibition of cAMP-Phosphodiesterase by biflavones of Ginkgo biloba <\i>in rat adipose tissue [J]. J Nat Prod， 1998， 61(11): 1386-1387.
[22]	SHIM SY， LEE S， LEE M. Biflavonoids isolated from Selaginella tamariscina<\i> and their anti-inflammatory activities via ERK 1/2 signaling [J]. Molecules， 2018， 23: 926.
[23]	SILVA GL， CHAI H， GUPTA MP， et al. Cytotoxic biflavonoids from Selaginella willdenowii<\i> [J]. Phytochemistry， 1995， 40(1): 129-134.
[24]	ZHANG GG， JING Y， ZHANG HM， et al. Isolation and cytotoxic activity of selaginellin derivatives and biflavonoids from Selaginella tamariscina<\i> [J]. Planta Med， 2012， 78(4): 390-392.
[25]	YANG C， SHAO YT， LI K， et al. Bioactive selaginellins from Selaginella tamariscina <\i>(Beauv.) Spring [J]. Beilstein J Org Chem， 2012， 8(1): 1884-1889.
[26]	HANAHAN D， WEINBERG RA. Hallmarks of cancer: the next generation [J]. Cell， 2011， 144(5): 646-674.
[27]	PORTT L， NORMAN G， CLAPP C， et al. Anti-apoptosis and cell survival: A review [J]. Biochim Biophys Acta， 2011， 1813(1): 238-259.

1.	肖国素，余洲，陈丽娜，吴玉婷，曹珊，张蕾，黄妮雯. 卷柏总黄酮通过调节Nrf2/HO-1信号通路减轻机械通气相关性肺损伤的机制. 西部医学. 2025(01): 5-9 . 百度学术
2.	吕雪峰，王莲萍，张明天，张莲珠，SONG Yu. 卷柏总黄酮的纯化工艺与细胞保护作用. 海南热带海洋学院学报. 2024(02): 104-112 . 百度学术
3.	孙允红，王晓晴，赵方舒，倪雯婷，尹怡铭，李保宏，侯林. 垫状卷柏的化学成分、药理作用现代研究及质量标志物(Q-marker)的预测分析. 中药药理与临床. 2023(11): 115-121 . 百度学术
4.	张莲珠，刘君，李驰坤，张雅剑，宋宇，成光宇. 卷柏总黄酮研究进展. 中国医药. 2022(03): 472-476 . 百度学术
5.	张应. 垫状卷柏提取物对体外肿瘤细胞生长抑制作用的研究. 中国校医. 2022(10): 785-787 . 百度学术
6.	吕华伟，李宇霞，罗蒙，江恒沛，张宏建，颜继忠. 垫状卷柏化学成分的研究. 中成药. 2021(01): 102-105 . 百度学术
7.	张应. 垫状卷柏提取物对人白血病细胞K562诱导凋亡的研究. 中国疗养医学. 2021(09): 913-914 . 百度学术