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Preventive and Therapeutic Effects of Chinese Herbal Compounds Against Hepatocellular Carcinoma

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Preventive and Therapeutic Effects of Chinese Herbal Compounds Against Hepatocellular Carcinoma molecules Review Preventive and Therapeutic Effects of Chinese Herbal Compounds against Hepatocellular Carcinoma Bing Hu 1,*, Hong-Mei An 2, Shuang-Shuang Wang 1, Jin-Jun Chen 3 and Ling Xu 1 1 Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; [email protected] (S.-S.W.); [email protected] (L.X.) 2 Department of Science & Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China; [email protected] 3 Department of Plastic & Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, The Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China; [email protected] * Correspondence: [email protected]; Tel.: +86-21-64385700 Academic Editor: Derek J. McPhee Received: 16 November 2015 ; Accepted: 20 January 2016 ; Published: 27 January 2016 Abstract: Traditional Chinese Medicines, unique biomedical and pharmaceutical resources, have been widely used for hepatocellular carcinoma (HCC) prevention and treatment. Accumulated Chinese herb-derived compounds with significant anti-cancer effects against HCC have been identified. Chinese herbal compounds are effective in preventing carcinogenesis, inhibiting cell proliferation, arresting cell cycle, inducing apoptosis, autophagy, cell senescence and anoikis, inhibiting epithelial-mesenchymal transition, metastasis and angiogenesis, regulating immune function, reversing drug resistance and enhancing the effects of chemotherapy in HCC. This paper comprehensively reviews these compounds and their effects on HCC. Finally, the perspectives and rational application of herbal compounds for HCC management are discussed. Keywords: hepatocellular carcinoma; Chinese herbal compound; phytopharmacology; prevention; treatment 1. Introduction Despite advances in diagnosis and treatment, hepatocarcinoma remains the sixth most common malignancy and the third principal cause of cancer deaths worldwide [1], underscoring the need to develop novel approaches for liver cancer control. Traditional Chinese Medicines (TCMs) play a positive role in the management of hepatocarcinoma [2,3]. TCMs are effective in alleviating clinical symptoms, improving quality of life and immune function, preventing recurrence and metastasis, delaying tumor progression, and prolonging survival of hepatocarcinoma patients [4]. Accumulated Chinese herbal compounds have been identified and demonstrated anti-cancer effects against hepatocellular carcinoma (HCC). Chinese herbal compounds represent an important medical and pharmaceutical resource for the development of new treatments for hepatocarcinoma. These compounds and their effects on HCC are comprehensively reviewed in present work. 2. Prevention of Hepatocarcinogenesis TCMs have long been used for disease prevention, including liver cancer. Increasing numbers of Chinese herbal compounds have been isolated and demonstrated preventive effects against hepatocarcinogenesis. Ursolic acid is a natural triterpenoid widely found in Chinese herbs, such as Gardenia jasminoides Ellis (Zhi-Zi), Prunella vulgaris (Xia-Ku-Cao) and Hedyotis diffusa Willd. Molecules 2016, 21, 142; doi:10.3390/molecules21020142 www.mdpi.com/journal/molecules Molecules 2016, 21, 142 2 of 26 Molecules 2016, 21, 142 2 of 25 (Bai-Hua-She-She-Cao). Ursolic acid is effective in preventing diethylnitrosamine (DEN)-induced She-She-Cao). Ursolic acid is effective in preventing diethylnitrosamine (DEN)-induced oxidative oxidative stress and hepatocarcinogenesis [5,6] (Figure1, Table1). stress and hepatocarcinogenesis [5,6] (Figure 1, Table 1). 17-19 Autophagy 14-16 Proliferation Tumor growth Apoptosis Cell 23-25 senescence 11-13 26 27-29 1 - 3 4 - 6 7 - 9 10 Drug resistance Hepatocarcinoma Anoikis Hepatocytes EMT Metastasis cells resistant 20-22 30-31 32-33 CD8+ T NK cells 34-35 Vascular Angiogenesis Regulatory T CD4+ T Dendritic cells endothelial cells 32,36 37-39 37-39 Positive effect Negative effect EMT, Epithelial–mesenchymal transition Figure 1. Anti-cancerAnti-cancer effects effects of of herbal co compoundsmpounds against hepatocarcinoma. 1, 1, Ursolic Ursolic acid; acid; 2, 2, Penta-acetyl geniposide; geniposide; 3, 3, Curcumin; Curcumin; 4, 4, Matrine; Matrine; 5, 5, Solamargine; Solamargine; 6, 6, Ponicidin Ponicidin;; 7, 7, Tetrandrine Tetrandrine;; 8, 8, BaicaleinBaicalein;; 9, 9, Bufalin Bufalin;; 10, 10, Ganoderiol Ganoderiol F; F; 11, 11, Rhein; Rhein; 12, 12, Oridonin Oridonin;; 13, 13, Curcumol Curcumol;; 14, 14, Salvianolic Salvianolic acid acid B; 15,B; 15,Steroidal Steroidal saponins saponins;; 16, 16, Davidiin Davidiin;; 17, 17, β-Elemene;β-Elemene; 18, 18, Ardipusilloside-I Ardipusilloside-I;; 19, 19, Raddeanin Raddeanin A A;; 20, 20, Tanshinone IIA; IIA; 21, 21, Cordycepin Cordycepin;; 22, 22, Huaier Huaier polysaccharides; polysaccharides; 23, Astragaloside 23, Astragaloside II; 24, II;Oroxylin 24, Oroxylin A; 25, TetramethylpyrazineA; 25, Tetramethylpyrazine;; 26, Arecoline; 26, Arecoline; 27, Artemisinin 27, Artemisinin;; 28, Resveratrol 28, Resveratrol;; 29, Isofraxidin; 29, Isofraxidin;30, Astragalus 30, polysaccharides;Astragalus polysaccharides; 31, Radix 31,GlycyrrhizaeRadix Glycyrrhizae polysaccharidespolysaccharides;; 32, Lycium 32, Lycium barbarum barbarum polysaccharide;polysaccharide; 33, Polysaccharides33, Polysaccharides from Artemisia from Artemisia annua L; annua 34, Gastrodin;L.; 34, Gastrodin;35, Shikonin; 35, 36, Shikonin;Gekko sulfated 36, Gekkopolysaccharide- sulfated proteinpolysaccharide-protein complex; 37, Gekko-sulfated complex; 37, glycopeptide; Gekko-sulfated 38, glycopeptide; Pedicularioside 38, G; Pedicularioside 39, Vitexin compound G; 39, Vitexin 1. compound 1. Table 1. Herbal compounds that inhibit hepatocarcinogenesis. Table 1. Herbal compounds that inhibit hepatocarcinogenesis. Targets/ Compounds Herbs Effects Ref. Molecular Events Targets/Molecular CompoundsGardenia jasminoides Ellis (Zhi-Zi), Herbs Effects Ref. Events Prunella vulgaris (Xia-Ku-Cao), ↓ DEN induced Ursolic acid ↓ Oxidative stress [5,6] Hedyotis diffusaGardenia Willd. jasminoides Ellis (Zhi-Zi), hepatocarcinogenesis Prunella vulgaris (Xia-Ku-Cao), Ó DEN induced Ursolic acid(Bai-Hua-She-She-Cao), etc. Ó Oxidative stress [5,6] Hedyotis diffusa Willd. hepatocarcinogenesis Penta-acetyl ↓ AFB1 induced Gardenia jasminoides(Bai-Hua-She-She-Cao), Ellis (Zhi-Zi)etc. ↓ GGT foci [7] geniposide hepatocarcinogenesis Ó AFB1 induced Penta-acetyl geniposide Gardenia jasminoides Ellis (Zhi-Zi) Ó GGT foci [7] Curcuma kwangsiensis (Yu-Jin or Er-Zhu), hepatocarcinogenesis C. phaeocaulis (Yu-Jin or Er-Zhu), ↓ DEN induced ↓ p21(ras), PCNA and Curcumin Curcuma kwangsiensis (Yu-Jin or Er-Zhu), [8] C. wenyujinC. (Yu-Jin phaeocaulis or (Yu-JinEr-Zhu), or Er-Zhu), hepatocarcinogenesisÓ DEN induced CDC2Ó p21(ras), PCNA Curcumin [8] C. longa (Yu-JinC. wenyujin or Jiang-Huang),(Yu-Jin or Er-Zhu), etc. hepatocarcinogenesis and CDC2 Coptis chinensisC. longa Franch.(Yu-Jin (Huang-Lian), or Jiang-Huang), etc. ↓ DEN-plus-PB induced ↓ iNOS, cytochrome P450, Berberine [9] PhellodendronCoptis chinense chinensis Schnied.Franch. (Huang-Lian),(Huang-Bai) hepatocyte proliferation CYP2E1Ó iNOS, cytochrome and CYP1A2 Ó DEN-plus-PB induced Berberine Phellodendron chinense Schnied. P450, CYP2E1 and [9] ↓ DENhepatocyte induced proliferation Saikosaponin-d Bupleurum(Huang-Bai) chinense (Chai-Hu) ↓CYP1A2 COX-2 and C/EBPβ [10] hepatocarcinogenesis Ó DEN induced Ó COX-2 and Saikosaponin-dthe fruits ofBupleurum Schisandra chinense chinensis(Chai-Hu) or ↓ 3′-MeDAB induced [10] Gomisin A hepatocarcinogenesis UnknownC/EBPβ [11] Schisandra sphenanthera (Wu-Wei-Zi) hepatocarcinogenesis the fruits of Schisandra chinensis or Ó 31-MeDAB induced Tea polyphenolsGomisin A ↓ DEN induced ↑Unknown p21WAF1 and Bax, [ 11] Tea Schisandra sphenanthera (Wu-Wei-Zi) hepatocarcinogenesis [12] and tea pigments hepatocarcinogenesis ↓ Bcl-2 Tea polyphenols and tea Ó DEN induced Ò p21WAF1 and Astragalosides, Tea [12] pigments hepatocarcinogenesis Bax, Ó Bcl-2 Astragalus Astragalus membranaceous (Huang-Qi), ↓ DEN induced ↓ GST-P and α-SMA [13] polysaccharideAstragalosides, and Salvia miltiorrhiza Bunge (Dan-shen) hepatocarcinogenesis Astragalus Astragalus membranaceous (Huang-Qi), Ó DEN induced Ó GST-P and salvianolic acids [13] polysaccharide and Salvia miltiorrhiza Bunge (Dan-shen) hepatocarcinogenesis α-SMA ↓ Inhibitsalvianolic or down-regulate, acids ↑ up-regulate; DEN,diethylnitrosamine; AFB1, aflatoxin B1; PB, phenobarbital; 3′-MeDAB,Ó Inhibit or 3′ down-regulate,-methyl-4-dimethylaminoazobenzene.Ò up-regulate; DEN, diethylnitrosamine; AFB1, aflatoxin B1; PB, phenobarbital; 31-MeDAB, 31-methyl-4-dimethylaminoazobenzene. Pentaacetyl geniposide, a component of G. jasminoides Ellis (Zhi-Zi), protects rats from aflatoxin B1 (AFB1)-induced hepatocarcinogenesis [7] (Figure 1). Curcumin, a common component present in Curcuma kwangsiensis (Yu-Jin or Er-Zhu), C. phaeocaulis (Yu-Jin or Er-Zhu), C. wenyujin (Yu-Jin or Molecules 2016, 21, 142 3 of 26 Pentaacetyl geniposide, a component of G. jasminoides Ellis (Zhi-Zi), protects rats from aflatoxin B1 (AFB1)-induced hepatocarcinogenesis [7] (Figure1). Curcumin, a common component present in Curcuma kwangsiensis (Yu-Jin or Er-Zhu), C. phaeocaulis (Yu-Jin or Er-Zhu), C. wenyujin (Yu-Jin or Er-Zhu) or C. longa (Yu-Jin or Jiang-Huang), is effective in preventing DEN-induced hepatocarcinogenesis accompanied by
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