|Year : 2015 | Volume
| Issue : 3 | Page : 101-107
Application and Perspectives of Traditional Chinese Medicine in the Treatment of Liver Cancer
Xia Mao, Yanqiong Zhang, Na Lin
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
|Date of Submission||03-Apr-2015|
|Date of Acceptance||06-Jun-2015|
|Date of Web Publication||30-Jun-2015|
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700
Source of Support: None, Conflict of Interest: None
Liver cancer is one of the most fatal cancers worldwide, the management of which demands a multidisciplinary approach. Conventional therapies such as surgery, chemotherapy, and radiotherapy have gained reasonable success. However, most of these patients experience a severe torment, both mentally and physically. Numerous studies have indicated that traditional Chinese medicine (TCM), when used in conjunction with conventional allopathic therapies, can enhance their efficacy and diminish the resulting side effects and complications. Therefore, a deeper understanding of TCM is of immense help to physicians and other health care providers in providing a better care to patients. TCM is proved to be efficacious in terms of suppressing tumor progression, improving immune system function, and increasing the sensitivity to chemo- and radio-therapies. Although TCM can be delivered in various dosage forms, pills, decoctions, and injections are the three most commonly used forms in treating liver cancer. While these traditional dosage forms limits the usage of herbal medicines to their full potential novel TCM delivery forms such as nanoparticles can enhance the bioavailability, reduce any associated side effect, achieve targeted delivery, and improve the acceptance of TCM by patients. This review summarizes the current application of TCM in different prescriptions and dosage forms in the treatment of liver cancer, along with their advantages and disadvantages, all of which is believed to contribute to better understanding of Chinese herbal medicines as an essential part in the treatment of liver cancer and the importance of this trend to combine TCM and western medicine in novel dosage forms for a better management of the condition.
Keywords: Liver cancers, therapy, traditional Chinese medicine
|How to cite this article:|
Mao X, Zhang Y, Lin N. Application and Perspectives of Traditional Chinese Medicine in the Treatment of Liver Cancer. Cancer Transl Med 2015;1:101-7
|How to cite this URL:|
Mao X, Zhang Y, Lin N. Application and Perspectives of Traditional Chinese Medicine in the Treatment of Liver Cancer. Cancer Transl Med [serial online] 2015 [cited 2019 May 25];1:101-7. Available from: http://www.cancertm.com/text.asp?2015/1/3/101/159538
| Introduction|| |
Liver cancer has emerged as a serious health concern worldwide as its morbidity and mortality rates continue to rise.  According to statistics, liver cancer is one of the rapid growing cause and ranks third in the "most common cause" of cancer-related deaths, attributing to its increased incidence and poor prognosis.  It is estimated that more than 800,000 people die of it worldwide every year.  In addition, liver being a common site of metastases, its involvement is estimated to lead to death of two-thirds of patients with colorectal liver metastases.  All these elevate "the need" for effective therapies to treat this disease. Over the past several decades, both traditional Chinese medicine (TCM) and western medicine have been applied in treating liver cancer. Due to the differences in their characteristics, both the systems shave their merits and demerits. Surgery, chemotherapy, and radiotherapy are conventional western medicine treatments that have gained reasonable success in reducing mortality. However, it is well acknowledged that most of these patients experience a severe torment, both mentally and physically, because of multiple side effects associated with this treatments.  Therefore, tumor patients seek complementary and alternative medicine (CAM) to help relieve their pain and improve their quality of life. TCM is considered to be a part of CAM and has been used in the treatment of cancer in China for more than 2,000 years. As an adjuvant therapy, TCM not only reduces the toxicity and adverse reactions caused by conventional western medicine but also will act synergistically with them.  As the use of TCM has been based on the empirical treatment, it falls behind western medicine in terms of mechanism elucidation and evidence-based data.  In addition, its traditional formulae and dosage forms need adjustment to maximize the therapeutic efficacy. This review summarizes the current application of TCM in different prescriptions and dosage forms in the treatment of liver cancer, presents their advantages and disadvantages, and is hoped to provide useful information for further studies on this combination therapy.
| The Application of Commonly Used Traditional Chinese Medicine in Liver Cancer Treatment|| |
Single herbs used in the treatment of liver cancer
Several single herbs have demonstrated the improvement of liver cancer conditions with multiple mechanisms. Brief frameworks on the pharmacology of commonly used single herbs are presented below [Table 1].
Astragalus membranaceus (Huangqi), one of the most common Chinese herbs, is widely used to prevent and treat variety of diseases and is the key-component in many Chinese herbal anti-tumor formulas. Much of the pharmacological research has shown that Huangqi has anticancer, immunomodulatory and anti-viral activity.  Astragalus saponins (AST) are the total saponins purified from the root of Huangqi and have anti-tumorigenic activity in several cancer cell types. It results in growth inhibition and promotes apoptosis of HepG2 cells through modulation of an ERK-independent nuclear factor kappa B (NF-kB) signaling pathway.  Moreover, AST could be an effective therapeutic agent in liver cancer treatment, which can be applied in combination with orthodox chemotherapeutic agents to potentiate their activity and reduce the associated adverse toxicity. 
Atractylodes macrocephala (Baizhu) has been used widely for deficiency syndromes and has shown noteworthy protective effect on liver injury. It has been noted to have numerous pharmacological activities including immunomodulation and antitumorigenesis. Studies have indicated that it reduces the serum interleukin-1 and tumor necrosis factor alpha levels and inhibits the expression of Bcl-2.  A. macrocephala polysaccharide (AMP) is one of the major active ingredients in A. macrocephala and has been reported to exert protective effects against hepatic ischemia-reperfusion injury in rats, which might be associated with its antioxidant properties and inhibition of NF-kB activation.  Clinically, it has been proved to potentiate the effect of chemotherapy and prolong survival in the treatment of liver cancer. 
Lobelia chinensis (Banbianlian) is a popular herb that has been widely used as folk medicine in China for the treatment of fever, liver cancer, and inflammation for hundreds of years and its main functions are heat-clearing and detoxifying. Experimental studies and clinical applications have indicated that it possesses various pharmacological activities such as immunomodulation, anti-cancer, and anti-viral.  It has been demonstrated to regulate the expression of p53 and inhibit cancer cells from dividing and synthesizing DNA and protein, thus promoting cancer cell apoptosis. 
Oldenlandia diffusa (Baihuasheshecao) is a well-known medicinal plant used to prevent and treat many disorders, especially cancers, and is famous for clearing heat and reducing toxicity. It possesses many biological activities such as immunomodulation, anti-cancer, and anti-viral. Ursolic acid, a triterpenoid compound isolated previously from O. diffusa, has been demonstrated to induce doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. 
Salvia miltiorrhiza (Danshen) is a typical TCM drug for promoting blood circulation and relieving blood stasis. Its pharmacological activities include anticancer, immunomodulation, anti-anaphylactic, and anti-inflammatory. Active compounds of S. miltiorrhiza protected the liver against fibrosis. This protection might have been due to the inhibition of p38 and NF-kB signaling in Kupffer cells, which subsequently reduced inflammation in the liver.  Moreover, compound from Astragalus and S. miltiorrhiza extract significantly suppresses hepatocellular carcinoma (HCC) progression by mediating TGF-β/Smad signaling, especially by modulating Smad3 phosphorylation both at the C-terminal and linker region.  It has also been demonstrated that their synergistic interactions with established anti-cancer drugs may provide significant contribution to their anti-HCCpotential. 
Carthamus tinctorius (Honghua), used in TCM, has many pharmacological effects, such as anticoagulant, antioxidant, anti-aging, and anti-tumor effects. It belongs to a group of Chinese herbs used for promoting blood circulation and relieving blood stasis. It has been proved to suppress liver cancer growth by inhibiting secretion of angiogenic factors.  Hydroxysafflor yellow A (HSYA), a flavonoid derived and isolated from traditional Chinese herb, C. tinctorius, could suppress messenger RNA expression levels of cell proliferation-related genes (cyclin D1, c-myc, and c-Fos) and improve spleen/thymus indexes, which was evaluated as the "immune system protective marker".  This study supports HSYA as a promising candidate for the prevention and treatment of HCC.
A survey shows that the branch of TCM that's mostly applied in the treatment of HCC is herbal medicine, as mentioned above. Among them, A. macrocephala (Baizhu) and A. membranaceus (Huangqi) are top two, most frequently used single herbs. Animal material medica, as an essential part of TCM, also plays an important role in the treatment of liver cancer.  For example, clinical experience has indicated that Carapax Trionycis (Biejia), Scorpion (Quanxie), and Scolopendra (Wugong) showed a positive effect when used for the treatment of liver cancer, and they have been indicated to inhibit the proliferation of HepG2 cells. 
Traditional herbal formulae used in liver cancer treatment
Traditional herbal formulae play their role in maintaining human beings health through the synergistic interaction and integrative action of each compound in it. A brief framework on the pharmacology of commonly used traditional herbal formulae is presented below [Table 2].
|Table 2: Traditional Chinese formulae commonly used in liver cancer treatment |
Click here to view
Shi-Quan-Da-Bu-Tang (SQDBT) is the most widely used traditional herbal formula in East Asia, also known as Sipjeondaebo-tang in Korea and Juzen-taiho-to in Japanese. It contains ten herbs including Angelica sinensis, Paeonia lactiflora, A. macrocephala, Poriacocos, Cinnamomum cassia, A. membranaceus, Liqusticum wallichii, Panax ginseng, Glycyrrhiza inflata, and Rehmannia glutinosa. It has been proved to exert anti-angiogenic effects in several tumor models.  In addition, SQDBT inhibits the growth of hepatic enzyme-altered lesions, suggesting that its effect may be in part due to activation of the immune system.  Moreover, clinical studies indicate that it is also effective in alleviating hepatotoxicity among patients receiving chemotherapy, without affecting the therapeutic activity of the drug. 
Xi-Huang-Wan (XHW) was prepared by a well-known Chinese physician Hongxu Wang during the Qing dynasty. It contains four herbs including Bos Taurus domesticus Gmelin, Boswellia carterii Birdw, Commiphora myrrha Eng1, and Moschus.  It has been used to treat several malignant cancers including liver cancer in the past and still serves the purpose. Further studies have shown that it can inhibit the expression of bcl-2, c-myc, and enhance the expression of p53 acting on Bel-7402 cell line, which may be related to cancer cell apoptosis. 
Bie-Jia-Jian-Wan (BJJW), a classic TCM formula, was originally recorded in "Synopsis of Golden Chamber" (Chinese name: Jin-Gui-Yao-Lue) written by Chinese medical sage Zhongjing Zhang. This traditional formula is used for promoting blood circulation and relieving blood stasis, which are consistent with the basic theory of TCM in the treatment of liver cancer. In recent years, there are many positive clinical reports on treatment of malignant tumors of esophagus, blood/bone marrow (leukemia), liver, and uterus (myoma) with BJJW.  It can significantly reduce the expression of β-catenin by decreasing the phosphorylation of GSK-3 β and blocking the Wnt/β-catenin signaling pathway, which may be one of the molecular mechanisms leading BJJW to suppress the proliferation and invasiveness of HCC.  Moreover, the anti-tumor effects of it might be associated with the inhibition of proliferating cell nuclear antigen expression.  In clinical settings, it is frequently used in combination with chemo- or radio-therapy as an adjuvant treatment in managing liver cancer. 
In addition to the formulae mentioned above, many more known prescriptions such as Huang-Lian-Jie-Du decoction, Shaoyao-Ruangan formula, Gansui-Banxia decoction, and Jiedu-Xiaozheng Yin have also been applied against hepatic cancer. There are certain prescription rules when treating liver cancer with TCM. Most frequently used medicine is tonifying medicine, in combination with heat-clearing medicine and blood-activating medicine. Based on the results of syndrome differentiation, other categories of TCM can be applied. 
| Different Dosage Forms of Traditional Chinese Medicine in Treating Liver Cancers|| |
Conventional dosage forms
Treatment based on syndrome differentiation is one of important theories in TCM, thus different dosage forms of TCM have diverse treatment outcomes. Different Chinese medicines are required to be designed in line with their characteristics in order to improve the efficacy and the bioavailability.  Conventional dosage forms such as decoctions, powder, ointment, pellet, and others have been applied in China for thousands of years. Every dosage form plays a role according to the characteristics of the dosage form itself. TCM injections (CTMJ), with modern advanced pharmaceutical technology, is a breakthrough in conventional dosage forms of TCM and has received more attention in recent years.  In China, different dosage forms of TCM have been widely applied in treating liver cancer in all aspects and has been confirmed to effectively inhibit cancer progression, improve quality of life, and prolong survival to a certain degree.  A brief outline of different dosage forms of TCM in liver cancer treatment is briefly presented below [Table 3].
Pills are first recorded in "prescriptions for 52 diseases" and are one of the most conventional dosage forms in TCM. The commonalities of pills are that the action is gentle and abiding, which is suitable for chronic disease. Several kinds of pills have been used in liver cancer treatment. XHW, Ma-Hong-Wan, and Shen-Tao-Ruan-Gan-Wan are the three representative pills in managing liver cancer. Among them, XHW is a well-known prescription in treating diverse malignant tumor cell strains and is effective in promoting blood circulation and relieving blood stasis. Several experiments have been conducted to demonstrate the rationale for selecting XHW. One such example is an experiment designed to compare the "anti-tumorigenesis effect of XHW by different processing methods." Leachate, decoction, and blood serum of XHW were used to treat malignant tumor cell strains. The results indicated that the leachate and decoction of XHW showed obvious inhibitory effects on cell multiplication of tumor cells, while blood serum showed no inhibitory effect, which proves the rationality and necessity of the dosage form of XHW.  Although pills are effective in treating liver cancer, they still are not the best dosage form. The problem is that its crude preparation process and large dosage leads to the limitation in deriving its maximum efficacy and decrease in the compliance of patients.
Decoction, created by Yin Yi in Shang dynasty, is one of the most ancient dosage forms of TCM in China. Its characteristics of "modification according to symptoms" can best embody the conception of treatment based on syndrome differentiation in TCM. Moreover, it has the advantages of easy absorption and rapid onset.  It is estimated that decoction is the most commonly used dosage form in liver cancer treatment in China. SQDBT, Xiao-Chai-Hu-Tang (XCHT), and Si-Ni-Tang (SNT) are three representative decoctions in treating liver cancer. It has been indicated that XCHT can markedly inhibit the growth of H22 mouse solid liver cancer and improve the immune function of tumor-bearing mice.  In clinical studies, it has been proved to be effective and safe in the treatment of advanced liver cancer.  SNT significantly inhibits the invasiveness and migration of tumor cells and has the advantage of minimizing toxicity of chemo- or radiation-therapy, when used in conjunction.  All these decoctions play a unique role in liver cancer treatment. However, its limitations such as inconvenient carriage, high administration dose, and unacceptable smell confine its wide usage in modern society.
CTMJ is the combination of traditional knowledge and modern technology, which conforms to the principle of including the essence and excluding the wastes of TCM as well as meets the demand of quick-acting on human beings.  Huachansu injection (HCJ), Shenmai injection, and Ganli injection are typical preparations in the treatment of liver cancer. HCJ is an aqueous extract from the skin and parotid venom glands of Bufo bufo gargarizans Cantor and widely used in tumor therapy, at clinical settings, in China. It has been indicated that HCJ can induce the apoptosis of HepG2 and Bel-7402 cells through a mitochondria-mediated apoptosis pathway. Clinical data showed that cinobufacini used alone or in combination with conventional chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) had significant anti-cancer activity against human cancers, such as HCC, nonsmall cell lung cancer, and pancreatic cancer.  TCMJ is good in treating acute or complicated diseases and makes up for the deficiencies of the oral rout. It also faces tremendous challenges and pressures due to its adverse reactions or even death caused by individual dosages. Thus, there is a necessity to improve and enhance the quality of TCMJ in order to minimize the risk. 
Novel traditional Chinese medicine delivery forms
Despite several modes of therapies such as conventional western medicine therapies and TCM therapies, applied in liver cancer treatment, it still remains a challenge to cure it. Nowadays, several nanotechnological approaches have been used to enhance delivery of TCM to tumor cells with the goal of maximizing anti-tumor efficacy and minimizing toxic effects on healthy tissues.  Nano-TCM refers to bioactive ingredients, bioactive parts, medicinal materials or complex prescriptions processed to the size of about 100 nm with different nanotechnological procedures, in view of different objects.  It has many advantages, for example, nano-TCM can achieve the targeted delivery and provide sustained release at the site if interest. Moreover, it enhances the bioavailability and pharmacological effects of TCM.
Several TCM have been prepared by nanotechnologies in liver cancer treatment by different preparation principles. For example, Himalayan yew, known as Thuner in Western Himalayas, has high medicinal value and is used to treat common infections among the local populations. In recent years, it has received wide attention as its leaves and bark were found to be the prime source of paclitaxel (PTX), which has a unique property of preventing the growth of cancerous cells and is used in the treatment of various kinds of cancers.  PTX is able to induce cell apoptosis and death. However, its drawback of high hydrophobicity limits its clinical application.  Dextran-based micelles loaded with PTX has been designed to overcome this drawback. This novel PTX nano-formulation was found to exhibit slightly stronger in vitro cytotoxicity against SKOV-3, OVCAR-8, and MCF-7 cells as compared to free PTX. Moreover, it effectively suppressed the tumor growth and highly reduced the toxicity when compared to free PTX in vivo. , S. miltiorrhiza (Danshen), as mentioned above, is a classical TCM for promoting blood circulation and removing blood stasis, with 1,000 years of clinical application. Recent data have demonstrated that its bioactive compounds tanshinones II A (DSIIA) shows potent anti-cancer activities both in vitro and in vivo.  However, its characteristics of fast metabolism and short half-life limits its wide usage.  Studies show that both DSIIA and DSIIA nanoparticle could inhibit the growth of hepatocarcinoma and prolong the survival time of mice. At the same time, the outcome of the nanoparticle-treated group is better than that of DSIIA treated group, at the same dosage. 
However, there still exist many problems that need to be solved in nano-TCM. The main challenge for nano-TCM is to maximize the knowledge of TCM and preparation techniques.
| Prospects|| |
Although TCM has benefitted one-fifth of the world's population in treating several diseases, its acceptance as a real therapeutic choice is still controversial.  Surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy are the main stream anti-cancer therapies currently being applied for controlling liver cancer and prolonging survival time. Recent preclinical and clinical studies have shown that TCM combined with conventional western medicine, early in the course of the disease and not at its terminal stages, can significantly improve the treatment outcomes.  One noteworthy example is Transcatheter arterial chemoembolization (TACE) combined with JDF. TACE is the most widely used primary treatment for HCC, but it carries potential risk of lung metastasis and causes liver function deterioration. JDF granule preparation, a commonly used TCM formula for HCC, is composed of cancer-fighting and detoxifying Chinese herbal medicines including root of Actinidia valvata and Salvia chinensis, bulb of Cremastra, appendiculata, and gizzard membrane of Gallus gallus domesticu. Clinical data have showed that TACE combined with JDF granule preparation could improve the prognosis and prolong survival of patients with HCC.  Some novel TCM delivery forms, such as nanoparticles, can enhance the bioavailability and pharmacological effects of TCM, and rectify the problems of conventional dosage forms. However, studies on the novel TCM delivery form mostly focus on the specific active ingredients, such as PTX and DSIIA, ignoring the other active ingredients which may act on liver cancer cells and also violate the principle of the wholeness of TCM. Therefore, it is necessary to set up a new model for nano-TCM to provide support. Combining conventional agents and modern biotechnological approaches to deliver TCM is a path set to promote the future practice of cancer. It is also worth noting that the studies on the mechanism of action of TCM in the treatment of liver cancer are still insufficient. Looking for more effective Chinese medicine and deep understanding of its mechanism of action will be a key to uncover its full potential in future.
Financial support and sponsorship
This study was supported by State Project for Essential Drug Research and Development (Grant number 2013ZX09301307), Beijing Nova program (Z1511000003150126) and the National Basic Research Program of China (973 Program) (2011CB505300, 2011CB505305).
Conflict of interest
There are no conflict of interest.
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[Table 1], [Table 2], [Table 3]