A survey on herbal management of hepatocellular carcinoma

Table 1 Summary of the effects of some herbs and other natural compounds on hepatocellular carcinoma

Compound	Ref.	Composition	Effect
Herbs with cancer chemotherapeutic effect
Geiji-Bokryung-Hwan	[78,79]	It is composed of five different herbs of Cinnamomi Ramulus, Poria Cocos Hoelen (Pachymae Fungus), Moutan Cortex Radicis, Paeoniae Radix, and Persicae Semen. The active constituents are antioxidative phenolic compounds, trans-cinnamic acid, taxifolin, protocatechuic acid, trans-o-hydroxy cinnamic acid, protocatechuic aldehyde, benzoic acid, trans-o-methoxy cinnamic acid, cis-o-methoxy cinnamic acid, 4-hydroxybenzoic acid, coumarin, daucosterol, Paeoniflorin, albiflorin and benzoylalbiflorin, paeonol and paeoniflorin.	The inhibitory effects of Geiji-Bokryung-Hwan (GBH) on the growth of cancer cell lines (HepG2 and Hep3B) and cancer chemopreventive activity were investigated. Tumor inhibition was found to be mediated via the inhibition of COX-1 activity.
Ganfujian granules	[80]	Ganfujian granules are an oral preparation consisting of dietary and medicinal Chinese herbs including Chinese yam (Rhizoma Dioscoreae), hawthorn fruit (Fructus Crataegi) and Chinese date (FructusZiziphi Jujubae). The active constituents are flavonoids including oligomeric procyanidins (OPCs), vitexin, vitexin 4'-O-rhamnoside, quercetin, and hyperoside	The herb was found to reduce and delay the incidence of diethylnitrosamine-induced hepatocarcinoma by exerting direct or indirect effects on the cell cycle and inhibiting uncontrolled proliferation of rat hepatocytes.
Maharishi amrit kalash	[81]	Maharishi Amrit Kalash (MAK) is composed of a mixture of two herbal mixtures, MAK-4 and MAK-5. The active constituents are multiple antioxidants including alpha-tocopherol, beta-carotene, ascorbate, bioflavonoid, catechin, polyphenols, riboflavin and tannic acid.	MAK was found to inhibit liver carcinogenesis when given as supplement to diet. The authors of this study suggested that the mechanism of this inhibition involved the prevention of excessive oxidative damage.
Scutellaria baicalensis and Bupleurum scorzonerifolfium willd	[43]	Chinese medicinal herbs. The active constituents are antioxidant flavonoids, baicalein, wogonin, neobaicalein, and skullcapflavone.	The these herbs were found to enhance the chemopreventive effect of selenium on N-nitosobis (2-oxopropyl) amine-induced liver cancers in Syrian hamsters.
Huqi san (Qi-protecting powder)	[28,82]	Huqi san is composed of eight medicinal herbs including (Ramulus Visci, Radix Astragali seu Hedysari, Radix Curcumae, Radix Salviae Miltiorrhizae). The active constituents are polysaccharides, flavonoids, alkaloids and tanshinones.	The inhibitory effect of Huqi san on rat prehepatocarcinoma, which was induced via diethylinitrosamine (DEN), was investigated. It was found to inhibit the over-expression of c-jun, c-fos, and c-myc oncogenes, which were shown to play an important role in the pathogenesis of hepatocellular carcinoma. Huqi san was also reported to inhibit DEN induced oxyradical formation in cultured hepatocytes, leading to suppression of oxidative DNA damage.
Milk thistle	[83,84]	Milk thistle, commonly known as silymarin, is extracted from Silybum marianum. The active constituents are flavonoids from which silibinin and silymarin are the biologically most active compound.	It has been shown that a topical application of silymarin on mice results in complete inhibition of an epidermal carcinogen and prevents the formation of pyrimidine dimers, which are considered to be potential skin cancer agents.
Herbs with cancer chemotherapeutic effect
Songyou Yin	[85]	This herbal extract is composed of a mixture of 5 Chinese medicinal herbs (Salvia miltiorrhiza, Astragalus membranaceus, lycium borbarum crataegus pinnatifida and trionyx sinensis). The active constituents are diterpenoid tanshinones, flavonoids and saponins.	"Songyou Yin" attenuates tumor proliferation and prolongs survival of nude mice bearing hepatocellular tumors without distinct toxicity. These findings suggest that "Songyou Yin" has some potential in the treatment of hepatocellular carcinoma.
Millettia reticulata benth	[86]	Millettia reticulata Benth is one of the oldest tonic herbs in traditional Chinese medicine. The active constituents are flavonoid derivatives: (-)-epicatechin, naringenin, 5,7,3',5'tetrahydroxyflavanone, formononetin, isoliquiritigenin, and genistein.	It was demonstrated that Millettia reticulata Benth flavonoid derivatives have a positive inhibitory effect on the viability of human cancer cells (including HepG2, SK-Hep-1, Huh7, PLC5, COLO 205, HT-29, and SW 872 cells). This Chinese herb also induces apoptosis in hepatocellular carcinoma cells via both Fas- and mitochondria-mediated pathways.
Bushen huayu jiedu recipe	[87]	"bushen huayu jiedu recipe" (BSHYJDR) is a mixture of several herbs including Chinese Cassia Bark, Psoralea, Zedoary, Rhubarb. The active constituents are alkaloids, flavonoid, arsenic trioxide, cinnamic acid, rhubarb and rhubarb substance.	BSHYJDR was found to inhibit transplanted hepatocarcinoma in mice. This effect is improved in combination with chemotherapy (cisplatin (DDP)).
Star 99	[88]	Chinese herbal compound	Human hepatocellular carcinoma was transplanted in nude mice and treated with Star 99 (intratumoral injection 10 days following to cancer transplantation). The herbal compound was shown to inhibit and destruct liver cancer cells, in particular the membrane, cytoplasm and nucleus of the caner hepatocyte.
Daesungki-Tang	[89]	This is a preparation consisting of four herbs: Rhei radix et rhizoma (the roots of Rheum coreanum Nakai), Aurantiii frutus immaturus (immature fruits of Poncirus trifolita Rafin), Magnoliae cortex (the stem bark of Magnolia officinalis Rehd. Et Wils), and Mirabilite (Matrii sulfas). The active constituents are magnolol, honokiol, physcion, chrysophanol, emodin, rhein, and aloe-emodin, naringenin glucuronide and hesperetin glucuronide.	This herb is widely used in the treatment of cancer metastasis. DST extracts were shown to inhib the invasion of the human hepatocellular carcinoma cell line, Hep 3B. On this basis, DST may be a promising antitumor agent.
Lycium barbarum and rehmannia glutinosa	[90]	Lycium barbarum (LBE) and Rehmannia glutinosa (RGE) are traditionally used as chinese medicines and herbal foods in China. The active constituents are beta-carotene, vitamin C, vitamins B1 and B2, beta-sitosterol, linoleic acid, immunologically active polysaccharides, sesquiterpenoids (cyperone, solavetivone), tetraterpenoids (zeaxanthin, physalin), and betaine .	Hot water-extracted Lycium barbarum (LBE) and Rehmannia glutinosa (RGE) were found to inhibit cell proliferation and induce p53 mediated apoptosis in hepatocellular carcinoma and inhibit oxidative DNA cleavage induced by various DNA damage chemicals. It also has immunological functions which lead to suppression of malignant cell growth.
Semen coicis	[91]	Semen Coicis is a traditional chinese herbal medicine which yields the extract Kang-Lai-Te (KLT). The active constituents are protein, fat, carbohydrate, vitamin B1, amino acids (leucine, lysine, arginine, tyrosine), Coix factors, Coix esters, triterpenoids.	KLT was found to inhibit HepG2 cell growth via a mechanism involving induction of apoptosis through activation of the Fas/FasL pathway.
Paeoniae radix	[58]	This crude drug from the root of Paeonia lactiflora Pallas is used in many traditional prescriptions in China and Japan. The active constituents are Paeoniflorin, albiflorin and benzoylalbiflorin.	Paeoniae Radix was found to inhibit the growth of hepatoma cell lines HepG2 and Hep3B via induction of apoptosis in a p53 independent pathway.
Qingrejiedu, huoxuehuayu, and fuzhengguben	[92]	Qingrejiedu, Huoxuehuayu, and Fuzhengguben (QHF) medicinal herbs. The active constituents are chlorogenic acid, geniposide, baicalin, forsythin, indirubin. ligustrazine chuanxiong, saponins, and isoflavonoids.	The QHF mixture was found to be more efficient in combating cancer than its separate ingredients. It was also reported to relieve symptoms that appear in patients with hepatocellular carcinoma and to decrease tumor growth by increasing the antitumor effect of cisplatin (DDP).
Delisheng	[93]	Delisheng is a n atural medicinal compound composed of ginseng, milk vetch root, secretion bufonis and cantharidium.	The activity of Delishng on the human hepatocellular carcinoma cell line HepG2 was investigated using the MTT assay, and compared to that of the chemotherapeutic drugs 5-fluorouracil and adriamycin. Delisheng was proved to have a positive anti-tumor activity, comparable to that of the chemotherapeutic drugs used.
Astragalus membranaceus	[94]	This herb, also known as aka huang chi, is one of the fundamental herbs used in traditional Chinese medicine. The active constituents are polysaccharides, saponins, flavonoids, amino acids.	The herb was found to improve the function of T lymphocytes in cancer patients compared with untreated cells.
Morarah and khaltita	[95]	Medicinal herbs. The active constituents is Kahalalide F.	Morarah and Khaltita were found to induce cell death in a heptoma (Huh-7) cell line, suggesting that these herbs could have a promising anti-cancer effect.

Possible molecular targets of herbal agents in different stages of hepatocarcinogenesis.