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

FANLian; WUYong-ping; QUHui; WUXin-hua; CAOYuan

Volume 35 Issue 6

Nov. 2019

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Article Navigation > Journal of Nanjing University of traditional Chinese Medicine > 2019 > 35(6): 664-670

FANLian, WUYong-ping, QUHui, WUXin-hua, CAOYuan. Selaginella Pulvinata Extract Exerts Antitumor Efficacy in H22 Tumor-Bearing Mice via Induction of Apoptosis[J]. Journal of Nanjing University of traditional Chinese Medicine, 2019, 35(6): 664-670.

Citation:

FANLian, WUYong-ping, QUHui, WUXin-hua, CAOYuan. Selaginella Pulvinata<\i> Extract Exerts Antitumor Efficacy in H22 Tumor-Bearing Mice via Induction of Apoptosis[J]. Journal of Nanjing University of traditional Chinese Medicine, 2019, 35(6): 664-670.

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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

Publish Date: 2019-11-10

Abstract

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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References(27)

References

[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]	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.

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

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