Use of herbal medicine in the treatment of liver cancer has a long tradition. The compounds derived from the herb and herbal composites are of considerable interest among oncologists. In the past, certain herbal compounds and herbal composite formulas have been studied through
Generally, the description of herbal medicine is the use of medicinal herbs, preparation made from a plant or plants, to prevent and treat diseases and ailments or to promote health and healing. However, it is important to distinguish “herbal medicine" and “herbal production", which is often overlooked [
A good example of herbal medicine is “Chinese herbal medicine", one branch of traditional Chinese medicine which focuses on naturalism and holistic health that can be traced back as far as 2100 BC in ancient China [
In general, the herbs used in herbal medicine often result from a combination of herbs with multiple ingredients, called “herbal composite formula", to ensure effective actions on multiple targets simultaneously. Contrary to Western medicine that prefers the analytical approach, most composite formulas in Chinese herbal medicine are empirically based and the principles underlining the composite formula are relatively simple; however, not as strongly defined and can vary among herbalists. A “food model" could be a good example to understand the principles consisting of the composite formula. Foods are complex and contain many different constituents. The furnished materials are used by body to nourish, support and reproduce its vital activities, while the wastes and some toxic materials are eliminated by the body itself. The rule of the composite formula and the dosage for an individual with specific signs and symptoms is also in the same way similar to the dosage of materials to treat marasmus and diet materials to treat obesity. Although the choice of herbs or “composite formula" for some specific signs and symptoms may represent in part a trend towards mysticism and thus highly variable, the fact is that some herbal drugs contain ingredients that specifically treat diseases. These biological ingredients extracted from natural substances result in multiple effective actions on different biological molecular targets.
Modern biomolecular science has contributed to the interpretation of these multiple effective actions of herbs, and some important properties such as anti-virus, anti-inflammatory and anticancer have been recognized. As more information is becoming available, some “herbal drugs" are identified for the effects against hepatocellular carcinomas (HCC). This aim of this review article is to present the current state of herbal medicine as a chemopreventitive and chemotherapeutic agent in HCC.
HCC is the fifth most common malignancy worldwide, and with a continuously increasing incidence [
Currently, few medical interventions have been thoroughly tested in HCC, in contrast with the many tested in other highly prevalent cancers, such as lung, breast and colorectal cancer [
In this article, for the sake of clarity, we divided the herbal medicine into effective herbal compounds and herbal composite formula to discuss their anticancer properties against HCC. Several reviews have provided major contributions to the current knowledge on the herbal medicines for treatment of liver fibrosis and cancer [
QUORUM algorithm of review of the herbal medicine publications and abstracts.
There are a number of molecular compounds derived from the herbs that have been proven to be effective against HCC. Modern research is confirming that many compounds are active at some molecular targets which are being sought to find out potential newer generation “targeted" biological response modifier drugs [
Summary of anti-HCC herbal compounds.
Compounds | Possible mechanisms of anti-HCC | References |
---|---|---|
Curcumin | Inhibits proliferation; induces apoptosis; inhibits p21(ras), PCNA, cyclin E, factor NF- | [ |
Resveratrol | Inhibits proliferation; induces apoptosis; downregulates Bcl-2 and upregulates Bax expression; reduces ROS; induces cell-cycle arrest in G1 and G2/M phases; modulates NO/NOS; increases gap-junctional intercellular communication; sharps increment of the mitochondria membrane potential; inhibits TNF-alpha-mediated MMP-9 expression; suppresses the ROS-potentiated invasion. | [ |
Silibinin | Causes G1 arrest; induces Kip1/p27; decreases cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)-2, and CDK4; downregulates metalloproteinase-2; increases acetylation of histone H3 and H4; inhibits cell proliferation; inhibits NO production and of ERK 1/2 cascade. | [ |
Tanshinone IIA | Induces apoptosis; induces cell arrested in G(0)/G(1); downregulates bcl-2 and c-myc; upregulates fas, bax, p53; inhibits DNA synthesis. | [ |
Summary results of the reported chemopreventitive effects of herbal compounds and herbal composite formulas.
Curcumin (diferuloylmethane), a compound extracted from
Curcumin has also been shown to have potent anti-metastatic activity. Ohashi et al. analyzed the anti-metastatic mechanism using an orthotopic implantation HCC model with CBO140C12 cells. They found that daily oral administration of curcumin suppressed intrahepatic metastasis of orthotopic implanted HCC cells. They further examined the effect of curcumin on the metastatic properties
Although numerous
Resveratrol, a polyphenol found in grape skins, peanuts, berries and red wine, has been shown to possess potent growth inhibitory effects against various human cancer cells including HCC. Resveratrol can be absorbed rapidly and accumulate in the liver. Lancon et al. studied the absorption and the efflux of resveratrol in the HepG2 cells. They found that resveratrol was rapidly conjugated and it entirely metabolized at 8 h to form two main resveratrol metabolites: monosulfate and disulfate [
Like curcumin, potent anti-metastatic activity of resveratrol has been also investigated. Yu et al. investigated the effects of resveratrol on invasion ability of human HCC cells and tumor necrosis factor-alpha (TNF-
Silibinin, a polyphenolic flavonoid, is the major biologically active compound of milk thistle. It is well known that milk thistle is safe and well-tolerated, and it protects the liver from drug or alcohol-related injury [
Currently, silibinin has not been evaluated for human effects or toxicity in human clinical trials and thus only holds potential promise as an active chemopreventitive agent.
Tanshinone IIA, one of the most abundant diterpenes isolated from
Beside these widely investigated compounds, some other potential compounds for the chemopreventive effect against HCC have been also evaluated. Salvianolic acid B is a major water-soluble polyphenolic acid extracted from
Besides these promising molecule compounds isolated or derived from herbals, there is a number of herbal complex formulas prescribed by Chinese medicine practitioners defined as either a traditional medical doctor or an herbal pharmacists for treating and preventing HCC. Using state-of-the-art technology, the techniques of herbal extraction and purification have been dramatically improved and innovated in the Chinese herbal medicine industry. The traditional forms of herbal preparation such as decoction, powder, plasters and pill have been developed into the modern forms, capsules, tablets and injection which as more convenient and palatable. The technological improvement of herbal preparation also made it becoming possible for better control the constituents of the herbal composite formula.
Although some herbal composite formula showed efficacy against HCC, it is worth mentioning that the usage of herbal composite formula is from the herbal medicine practitioner’s point of view which is quite different from that of conventional Western medicine, that is, not validated in a standard Phase 1, Phase 2 or Phase 3 clinical trials. When a formula is composed using different herbs, from the herbal medicine principle, the whole unhealthy condition should be treated to make body homeostasis other than to “cure" tumor only. Generally, herbal composite formula can be divided into two categories: classic composite formula and experience composite formula. Classic composite formula is an ancient formula with definite constituent of herbs. Classic composite formula can be traced back as far as thousands years, while experience composite formula is a contemporary composite formula which is generally modified from classic composite formula. Experience composite formula is usually not with definite constituent of herbs, and the constituent of composite formula can be changed with addition or deletion of herbs according to the symptoms of patients. Both classic composite formula and experience composite formula are discussed and summarized in Table
Summary of anti-HCC herbal composite formula.
Herbal composite formula | Possible mechanisms of anti-HCC | References |
---|---|---|
Shi-Quan-Da-Bu-Tang (TJ-48) | Inhibits tumors growth, reduces oxidative DNA damage, inflammatory cell infiltration and cytokine expression | [ |
Sho-saiko-to (TJ-9) | Increases TNF- | [ |
Bu-Zhong-Yi-Qi-Tang | Stimulates productions of G-CSF and TNF- | [ |
Shenqi mixture (SQM) | Increases CD3+, CD4+, CD4+/CD8+, NK activity | [ |
Xiaoliu Pingyi Mixture (XLPY) | Inhibits growth; induces apoptosis; inhibits Bcl-2 gene | [ |
Sihoga-Yonggol-Moryo-Tang (SGYMT) | Inhibits MMP-2 and MMP-9; inhibits tumor invasion | [ |
QHF | Inhibits the growth of HCC | [ |
Fuzheng Jiedu Decoction (FJD) | Enhances PTEN; inhibits tumor invasion | [ |
Star-99 | Inhibits the growth of HCC; induces apoptosis | [ |
Shi-Quan-Da-Bu-Tang (TJ-48, Juzen-taiho-to in Japanese,) is a classic herbal composite formula. It consist of 10 herbs; Mongolian milkvetch root, Cinnamon, ginseng root, largehead atractylodes rhizome, tuckahoe, liquorice root, Chinese angelica, radix rehmanniae root, white peony root, szechwan lovge rhizome. TJ-48 has been used extensively in medical practice in Asia even though their mechanism of action remains elusive. Tsuchiya et al. studied the protective effect of TJ-48 against hepatocarcinogenesis in HCC patients after surgical treatment. A significantly longer intrahepatic recurrence-free survival was observed in the TJ-48 group even though most of the patients experienced recurrence of HCC [
Xiao-Chai-Hu-Tang (TJ-9, Sho-saiko-to in Japanese), a classic herbal composite formula, is commonly administered to patients with chronic viral liver disease in order to improve their overall physical condition and to prevent the development of liver cancer. The crude extracts of TJ-9 consist of seven herbs: bupleurum root, pinellia tuber, scutellaria root, jujube fruit, ginseng root, glycyrrhiza root and ginger rhizome. A prospective, randomized, non-blind controlled study was carried out by Oka et al. to evaluate the preventive effect of TJ-9 on HCC development. Two hundred and sixty patients with cirrhosis were randomly assigned to two groups, matched for age, sex, presence of hepatitis B surface antigen and the severity of liver damage. The patients in the trial group were given TJ-9 at a daily oral dose of 7.5 g in addition to the conventional drugs given to the control patients, and prospectively monitored for 60 months. They found that the survival curve for 5 years of the trial group without Hepatitis B antigen was significantly higher than that of the control group. They concluded that TJ-9 could help to prevent the development of HCC in patients with cirrhosis, particularly in patients with negative hepatitis B antigen [
Bu-Zhong-Yi-Qi-Tang (BZYQT) is a classic herbal composite formula in Chinese herbal medicine, it consist of eight herbs; Mongolian milkvetch root, liquorice root, largehead atractylodes rhizome, ginseng root, Chinese angelica, skunk bugbane rhizome, bupleurum root and tangerine. Kao et al. investigated the effects of BZYQT on granulocyte colony-stimulating-factor (G-CSF) and TNF-
Because the focus of composing a formula is not in the direct “killing" of tumor cells, herbal composite formula is usually considered as palliative treatment and adjuvant treatment for HCC. The purpose for clinical use of experience herbal composite formula is to recover liver function, alleviate symptoms and to improve life quality. Most studies of use of experience herbal composite formula are retrospective, and the constituent of herbs in composite formula is not well defined. The experience herbal composite formula usually combines with the conventional palliative treatment such as transcatheter arterial chemoembolization (TACE) and systemic chemotherapy (Table
Summary of clinical reports using herbal medicines to treat patients with HCC.
Classic herbal composite formula | Patient numbers (treated/control) | Dosing and duration | The anti-HCC effects | Refs |
---|---|---|---|---|
Shi-Quan-Da-Bu-Tang (TJ-48) | 48 (10/38) | 7.5 g daily oral dose. For up to 6 years | Inhibiting tumors growth. Improving intrahepatic recurrence-free survival after surgical treatment of HCC | [ |
Sho-saiko-to (TJ-9) | 260 (130/130) | 7.5 g daily oral dose. For up to 2.5 years | Preventing the development of HCC in patients with cirrhosis, particularly in patients with negative HBs antigen | [ |
Shenqi mixture (SQM) combined with microwave coagulation | 72 (36/36) | 20 ml, three times a day for 1 month | Improving clinical symptoms and the quality of life. Prolong the survival period of patients | [ |
Complex prescription of Chinese crude drug after TACE therapy | 82 (45/37) | Dosing unavailable. Duration 1 month | Reducing the side effect of TACE. Improving liver function and life quality | [ |
Complex prescription of Chinese crude drug combined with TACE therapy | 2653 (unavailable/unavailable) | Dosing and duration unavailable | Improving patient survival and life quality. Alleviating symptoms. Increasing tumor response | [ |
Complex prescription of Chinese crude drug combined with chemotherapy | 2079 (unavailable/unavailable) | Dosing and duration unavailable | Improving survival rate and tumor response | [ |
A retrospective study was undertaken by Chen et al. to evaluate the effect of a complex prescription of Chinese crude drug on the hepatic function and some symptoms in HCC patients post-TACE. Forty-five HCC patients post-TACE were treated with a complex prescription of herbal crude, other 37 patients as the control group treated by routine therapy. The symptoms such as anorexia, nausea, abdominal distention and lassitude along with liver function and
Meng et al. performed meta-analysis to compare the efficacy and safety of complex prescription of Chinese crude drug plus TACE (therapy I) with that of TACE alone (therapy II). In total, in 37 trials involving 2653 patients, the results showed that therapy I, compared with therapy II, improved patient survival, quality of life, alleviated symptoms and increased tumor response. Combining of complex prescription of Chinese crude drug with TACE are thus more therapeutically beneficial. No serious adverse events were reported in therapy I group [
Shu et al. evaluated the effectiveness of Chinese herbal medicine combined with chemotherapy. They searched the databases TCMLARS, PubMed and EMBASE as well as the bibliographies of studies identified in the systematic search for potentially relevant titles or abstracts of studies in any language. They applied random effects meta-analysis in 26 studies representing 2079 patients met the inclusion criteria. They found that Chinese herbal medicine combined with chemotherapy improved survival rate and tumor response compared with chemotherapy alone [
Shenqi mixture (SQM) is an herbal composite formula from Ginseng root and Mongolian milkvetch root
The
TJ-9, as a typical classic composite formula, has been investigated regarding its anti-HCC effect. The ingredients from this classic composite formula have been also evaluated widely to explore more efficient l compounds against HCC. Yamashiki et al. investigated the effect of TJ-9 on TNF-
Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (SGYMT; Saiko-ka-ryukotsu-borei-to in Japanese; Sihoga-Yonggol-Moryo-Tang in Korean) is a classic composite formula. The crude extracts of SGYMT consist of 11 herbs: bupleurum root, dragon's bone, rhubarb, pinellia tuber, scutellaria root, cassia twig, rhubarb, jujube fruit, ginseng root, glycyrrhiza root and ginger rhizome. Ha et al. studied the extracts prepared from SGYMT and its herbal ingredients for the inhibitory effects on tumor-specific matrix metalloproteinases-2 and -9 (MMP-2/9) activities in HCC cell line (SK-Hep1 cells). They found that SGYMT decreased the activities of MMP-2 and -9. However, the cytotoxicities of SGYMT and its ingredients on SK-Hep1 cells were very low. The inhibitory effect on the invasion of SK-Hep1 cells using matrigel precoated transwell chambers showed that SGYMT effectively inhibited the invasion of SK-Hep1 cells as compared to the control groups. They concluded that SGYMT could be used as potential anti-tumor metastasis agent [
QHF is an herbal composite formula including three category herbs (according to Chinese herbal principle), in which Q (Qingrejiedu) represents “clean up pathogenic and toxic materials"; H (Huoxuehuayu) represents “improve micro blood circulation"; and F (Fuzhengguben) represents “enhance defending capability". QHF consist of mainly by Ginsenosides Rg3, Lentinan, Tanshinone and Norcantharidin. Chen et al. investigated the active ingredients in QHF formula against HCC. They observed the anti-HCC effect of QHF combined with cisplatin in a HCC cells implanted mouse model. The results indicated that treatment with the QHF formula was efficient not only in inhibiting the growth of HCC cells, but also in prolonging the life of the HCC mice. In addition, QHF combined with cisplatin can ameliorate cisplatin-induced leucopenia, spleen and thymus atrophy and other toxic reactions [
Yin et al. investigated the effect of Fuzheng Jiedu Decoction (FJD), an experience composite formula, against HCC using male BALB/c athymic mouse model. They observed survival rate, volume of tumors, and intrahepatic metastasis. The results indicated that FJD significantly increased the total survival rate and decreased tumor intrahepatic metastasis. Immunohistochemistry showed that an increased intensity of phosphatase and tensin homolog deleted on chromosome ten (PTEN) staining in tumor tissue treated with FJD. They concluded that FJD can prolong the survival and decrease tumor intrahepatic metastasis. The possible mechanisms of FJD against HCC could be through enhancing the expression of PTEN in the compromised liver [
Lin et al. investigated the anti-cancer effect by tumor focal injection of Chinese herbal composite formula Star-99 in a HCC mouse model. Nude mice transplanted with human HCC SMMC-7721 cells were intratumorally injected with Star-99 every 5 days with a total of four injections. Tumor value, growth index and apoptosis were evaluated. They found that Star-99 can decrease the tumor size, and increase apoptotic index significantly. They concluded that Star-99 markedly destructs HCC cells
Qian et al. used
There are some
Through centuries of clinical practices in herbal medicine, there could be a number of candidate drugs derived from the herbs or herbal composites formulae for chemoprevention and chemotherapeutic strategy against HCC. Certain herbal compounds and herbal composite formula have been studied through
The third is concern about the safety of herbal remedies. Traditional medical doctor, or herbal pharmacists recommend the traditional forms of herbs that are organic, unadulterated, unprocessed and prepared in traditional ways, just like any dietary ingredient, the processing methodologies are described in Chinese, Japanese, Korean Pharmacopoeias. They simply trust the wisdom of the body to recognize and make use of herbs. However, the reports of the herbal toxic effects contradict the popular view that herbals are natural and harmless. Among the herbal toxic effects, hepatotoxicity is the most frequent. The investigation of compounds and composite formula regarding safety and toxicity is needed before definitive clinical guidelines can be made.
Thus in summary herbal compounds have been shown to be efficacious and safe in small single center studies in the treatment and prevention of HCC and cirrhosis. However, on going standardization of the preparation, purity, and active compounds in conjunction with natural constituents should be specified for quality control aspects and must be established in order for future Phase 2 and Phase 3 trials can be created to verify these intriguing and optimistic results in this devastating disease.
The project described was supported by Award Number R03CA137801 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.