2. Chinese medicine as the source of discovering new treatment for liver cancer

As mentioned above, currently there are various therapies for liver neoplasm. However, the overall survival rate of patients still remains unsatisfactory on account of high invasiveness and metastasis, chemotherapeutic resistance, and so on. Chinese medicine, in various forms including composite formulae, extracted fractions, monomers, and their derivatives, has been pursued as ideal and novel sources for therapeutic agent development for cancer.

#### 2.1. Single compounds from Chinese medicine for the treatment of liver cancer

Over the past decades, the clinical approaches to treat liver cancer have considerably evolved. Patients can benefit from partial hepatectomy, radiotherapy, systemic or local chemotherapy, liver transplantation, and radiofrequency ablative surgery. Nevertheless, numerous adverse events and dismal outcomes still seriously affect the life quality of patients. On the background of shortcom-

Considering its low toxicity and high activity, Chinese medicine has been deemed as one of the prominent complementary and alternative approaches in tumor therapy. As unique biomedical and pharmaceutical resources, Chinese medicine owns the ability of providing better treatment for liver cancer, either alone or in integrative way [3]. According to Hong Kong Liver Cancer staging system in a population-based investigation, for patients with Va/Vb (tumor status being early, intermediate or locally advanced), the most frequent treatment was Chinese medicine [4]. Another cohort study in Taiwan reported that Chinese medicine users exhibited significant lower risk to suffer HCC, which supported the application of Chinese medicine into the clinical practice of liver cancer treatment [5]. A recent meta-analysis showed that add-on therapy with Chinese medicine regimens in HCC could reduce side effects, activate tumor responses, and improve overall survival. Moreover, cancer subjects were reported to be more inclined to integrating Chinese medicine regimens with conventional therapies rather than conventional treatment only [6]. In this regard, Chinese medicine has been considered as a potential curative choice of method for controlling the proliferation of liver cancer, and thus improving the quality of life and

Historically, the medical foundation of Chinese medicine can be traced back to 5000 years ago. With contributions and dedications of Chinese medical people in modern and old times, Chinese medicine has been gradually evolved and accepted by the mainstream society. In particular, accompanying the tide of Chinese immigration and cultural communication, Chinese medicine has been approved worldwide and employed in clinical practice in at least 183 countries [7]. Even though many regions have the regulations imposing restrictions to ensure that Chinese medicine is beneficial to liver cancer patients instead of being harmful to public

However, due to its effective curative outcomes in real life, the usage of Chinese medicine in various forms of single compounds, extracted fractions, and composite formulae has attracted a great deal of attentions over the past few decades. Chinese medicine may be capable of retarding liver cancer progression with its multitargets and coordinated intervention actions, either in combination with conventional therapies or radiation alone. Here, we retrospectively reviewed

and analyzed the functional roles of Chinese medicine in the treatment of liver cancer.

2. Chinese medicine as the source of discovering new treatment for liver

As mentioned above, currently there are various therapies for liver neoplasm. However, the overall survival rate of patients still remains unsatisfactory on account of high invasiveness

health, the evidence-based guideline has not been covered every field [8, 9].

ings, developing improved preventive and therapeutic strategy is urgently necessary.

prolonging overall survival of the patients.

cancer

114 Liver Cancer

Berberine is a natural product in many Chinese medicinal herbs, especially Coptidis rhizoma, which has been extensively studied and reported to show the antitumor action mostly by modulation of a number of different signal transductions. Currently, scholars have explored the antitumor action of berberine in liver cancer by various different strategies. For instance, in our laboratory, we found that berberine-induced cell death and tumor growth inhibition in xenograft model were demonstrated and mechanism was revealed that miR-23a might play a mediated role in berberine-suppressing HCC growth [10]. Also, cyclin D1 overexpression is mainly responsible for tumor expansion, metastasis as well as angiogenesis. Berberine was found to repress the expression of cyclin D1 via proteasomal degradation in HCC [11]. In addition, our group identified that berberine exerted antimigratory and anti-invasive abilities in HCC cells involving the upregulation of PAI-1 and downregulation of uPA [12]. On the other hand, our group described for the first time that berberine could trigger autophagic cell death, in which the compound was shown to activate Beclin-1 and suppress mTOR [13]. Actually, lung metastases in liver cancer are also a serious problem for patients, and we identified that the anti-invasive and antiproliferative actions of berberine in liver cancer was at least in part involved in the downregulation of Id-1, revealing a new anti-invasive mechanism [14]. Hence, berberine is predicted as a new and potent natural molecule targeting liver cancer.

Flavonoids commonly exist in Chinese medicine and could be isolated from many different kinds of herbal medicine. In recent years, the precise molecular mechanism underlying the obvious antiliver tumor effect of flavonoids has been studied. For example, hydroxysafflor yellow A (HSYA), a kind of flavonoid extracted from Carthamus tinctorius L. owns the ability of antitumor. It was demonstrated that HSYA could result in angiogenesis inhibition of HCC by blocking signaling pathways of ERK/MAPK and NF-κB in comparison with negative control group. More interestingly, spleen and thymus indexes have been demonstrated to be improved, suggesting improvement on the immune system by HSYA [15]. Oroxin B (OB) is one of the flavonoids isolated from Oroxylum indicum (L.) Vent. Li et al. investigated the antitumor effects of OB on HCC cell line SMMC-772 and studied the underlying mechanisms by which OB markedly inhibited expansion and induced apoptosis of the HCC cells. The antitumor activity of OB probably involved the inhibition of COX-2/VEGF and PTEN/PI3K/AKT signaling pathways, providing evidence for OB being used as a new therapeutic agent for liver cancer [16]. Another flavonoid, namely luteolin, showed antineoplastic activity in a number of cancer cells. In SMMC-7721 HCC cells, luteolin induced apoptosis partially via modulation of autophagy, indicating luteolin serving as a regulator of autophagy in treating liver cancer [17].

Brucein D (BD) is an active constituent derived from Brucea javanica fruit, which has been employed as an antitumor recipe in Chinese medical practice. It was revealed that BD exerted observable apoptotic induction in HCC in vitro and in vivo, which was attributed to the reduced expression of miR-95 [18].

Matrine, a chemical component came from the roots of sophora species, mainly Sophora flavescens Ait (SF), has been used clinically to treat diseases such as liver fibrosis. The hepatospecific miR-122a has been found decreased in HCC cell lines [19]. Zhou et al. reported that in HepG2 cells, matrine could cause cell arrest alteration as well as apoptosis induction with recovering expression of miR-122a [20]. Actually, matrine is the prominent bioactive compound in one adjuvant treatment of liver cancer, namely Fufang Kushen injection, which was approved by Chinese FDA in 1995. Matrine has been deemed as the favorable lead source for drug discovery owing to its changeable structure and stable safety profile. Researchers designed and synthesized a group of matrine derivatives, which improved the antitumor activities of matrine in several human cancer cell lines. Among four tested cell lines, HCC cell line Bel-7402 responded more sensitively to compounds than the other three cell lines. Matrine and its derivatives induced G1 cell cycle blockage as well as migration inhibition in HCC cells [21]. Another matrine derivative named WM622 showed remarkable inhibitory effect on HCC both in vivo and in vitro. Further study showed the apoptotic induction, cell cycle blocking in G0/G1 phase and the inhibition of PI3K/AKT signaling were involved in the antiliver cancer effect of WM622 [22].

and induced apoptosis of HCC cells via AMPKα-mediated suppression of Sp1, followed by suppressing DNMT1 expression. The investigation revealed a potential novel mechanism by which UA controlled proliferation of HCC cells, suggesting the critical effect of DNMT1 in

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 117

Bilobol is a Chinese medical ingredient. Xu et al. identified that bilobol administration could suppress expansion of HepG2 cells, which pretreated with lipopolysaccharide (LPS) to induce inflammation. Bilobol appeared to exhibit antitumor effect via inhibiting the RhoA/ROCK

Fucoidan, a sulfated polysaccharide isolated from brown algae, has been applied as an anticancer drug for hundreds of years in Chinese medicine. The results from Zhu et al. revealed that fucoidan had the capacity of antitumor partially through inhibiting the proliferation of HCC cells, although it is unable to repress the angiogenesis induced by HCC [29]. In another study, fucoidan displayed the antimetastatic efficacy on HCC cell lines via upregulating p42/44 MAPK-dependent NDRG-1/CAP43 pathway. Also, fucoidan was found to protect against bile acid-induced hepatocyte apoptosis. This ability suggested fucoidan presented a potent thera-

Telekin is a eudesmane-type sesquiterpene lactone extracted from the natural plant Carpesium divaricatum, which presents strong antiproliferative activity in cancer cells. Zheng et al. found that telekin promoted HCC cells apoptosis by activating the mitochondria-mediated apoptotic

Gigantol is a phenolic substance derived from the genus Dendrobium. Chen et al. investigated gigantol efficacy on liver cancer cells and the results suggested gigantol inhibited cells expansion and induced apoptosis in HepG2 cells through PI3K/Akt/NF-kappaB signal transduction [32]. The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play critical roles in the modulation of cell fate. The two factors even could become potent targets and provide support for the development of antineoplastic agents. Celastrol, one of the triterpene compounds derived from herbal medicine, exerts antitumor effects on various malignancies. Ren et al. demonstrated that for HCC cells, exposure to celastrol led to the sensitivity of the intrinsic apoptotic pathway, at least partly through ER stress and the UPR. Moreover, celastrol was found to repress H22 tumor growth in murine syngeneic model studies by inducing ER stress and apoptosis. These data suggested that targeting ER-stress/UPR was an efficient way for celastrol becoming a potent drug for HCC therapy [33]. Cytisine, a quinolizidine alkaloid, also a major bioactive constituent purified from the Sophora alopecuroides L. It was reported to exhibit inhibitory effects in treating liver cancer by inducing the ER stress-mediated apoptotic pathway through activating CHOP, JNK, and caspase-4 signaling pathways in liver cancer cells. This

phenomenon suggested a novel target compound potentially to treat liver cancer [34].

RA-XII, a naturally occurring compound originated from Chinese herbal medicine Rubia yunnanensis, possesses activities of anti-inflammatory and antitumor. Song et al. revealed that RA-XII accelerated apoptosis and repressed protective autophagy via signaling pathway AMPK/ mTOR/P70S6K in HepG2 cells, suggesting RA-XII, a cyclopeptide, provides the therapeutic support for potentially being an autophagy inhibitor drug in the therapy of hepatic tumor [35].

HCC chemoprevention and treatment [27].

peutic agent for HCC treatment [30].

pathway [31].

signal transduction during the anti-inflammatory response [28].

Longikaurin A (LK-A) is a naturally occurring compound of ent-kaurane obtained from I. aternifolius. Researchers explored LK-A administration in liver of tumor-bearing mice models and discovered that LK-A could induce cell cycle arrest at G2/M phase with downregulation of Skp2 and subsequently resulted in induction of ROS/JNK/c-Jun apoptotic pathway in HCC cells [23].

The antitumor of two known pennogenyl saponins, which are derived from R. paridis axialis, was investigated in orthotopic nude-mouse model. The data indicated that these two monomers dose dependently suppressed the HCC progression through activating both caspaseindependent and caspase-dependent apoptotic pathways. Furthermore, possible mechanism probably involved the modulation of mitogen-related protein kinase pathway as well as the suppression of PI3K/Akt signaling [24].

Isoquercitrin was found to strongly repress liver tumor cells via retarding the G1 phase cell cycle and promoting cancer cells apoptosis. In nude mice, the proliferation of transplanted tumors was suppressed after treatment with isoquercitrin. Further study showed that the underlying mechanism might be closely involved in the MAPK and PKC signaling pathways [25].

Zhang et al. investigated the effect of astragaloside IV (AS-IV) and curcumin on tumor expansion and angiogenesis in nude mice bearing xenografts of HCC. Combining AS-IV and curcumin revealed significant synergistic repressive efficacy against both angiogenic and thrombosis-related factors, which might be mediated by downregulation of miR-221 as well as upregulation of miR-122. This current study indicated future clinical potential of combination therapy with AS-IV and curcumin for treatment of liver cancer [26].

Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid carboxylic acid found among Chinese herbal medicine, has been reported to be a potent component for cancer prevention, including liver cancer. Yie et al. explored the probable mechanisms underlying the antiliver cancer action of UA. Taken together, the results demonstrated that UA inhibited proliferation and induced apoptosis of HCC cells via AMPKα-mediated suppression of Sp1, followed by suppressing DNMT1 expression. The investigation revealed a potential novel mechanism by which UA controlled proliferation of HCC cells, suggesting the critical effect of DNMT1 in HCC chemoprevention and treatment [27].

Matrine, a chemical component came from the roots of sophora species, mainly Sophora flavescens Ait (SF), has been used clinically to treat diseases such as liver fibrosis. The hepatospecific miR-122a has been found decreased in HCC cell lines [19]. Zhou et al. reported that in HepG2 cells, matrine could cause cell arrest alteration as well as apoptosis induction with recovering expression of miR-122a [20]. Actually, matrine is the prominent bioactive compound in one adjuvant treatment of liver cancer, namely Fufang Kushen injection, which was approved by Chinese FDA in 1995. Matrine has been deemed as the favorable lead source for drug discovery owing to its changeable structure and stable safety profile. Researchers designed and synthesized a group of matrine derivatives, which improved the antitumor activities of matrine in several human cancer cell lines. Among four tested cell lines, HCC cell line Bel-7402 responded more sensitively to compounds than the other three cell lines. Matrine and its derivatives induced G1 cell cycle blockage as well as migration inhibition in HCC cells [21]. Another matrine derivative named WM622 showed remarkable inhibitory effect on HCC both in vivo and in vitro. Further study showed the apoptotic induction, cell cycle blocking in G0/G1 phase and the inhibition of PI3K/AKT signaling were involved in the antiliver cancer

Longikaurin A (LK-A) is a naturally occurring compound of ent-kaurane obtained from I. aternifolius. Researchers explored LK-A administration in liver of tumor-bearing mice models and discovered that LK-A could induce cell cycle arrest at G2/M phase with downregulation of Skp2 and subsequently resulted in induction of ROS/JNK/c-Jun apoptotic pathway in HCC

The antitumor of two known pennogenyl saponins, which are derived from R. paridis axialis, was investigated in orthotopic nude-mouse model. The data indicated that these two monomers dose dependently suppressed the HCC progression through activating both caspaseindependent and caspase-dependent apoptotic pathways. Furthermore, possible mechanism probably involved the modulation of mitogen-related protein kinase pathway as well as the

Isoquercitrin was found to strongly repress liver tumor cells via retarding the G1 phase cell cycle and promoting cancer cells apoptosis. In nude mice, the proliferation of transplanted tumors was suppressed after treatment with isoquercitrin. Further study showed that the underlying mech-

Zhang et al. investigated the effect of astragaloside IV (AS-IV) and curcumin on tumor expansion and angiogenesis in nude mice bearing xenografts of HCC. Combining AS-IV and curcumin revealed significant synergistic repressive efficacy against both angiogenic and thrombosis-related factors, which might be mediated by downregulation of miR-221 as well as upregulation of miR-122. This current study indicated future clinical potential of combina-

Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid carboxylic acid found among Chinese herbal medicine, has been reported to be a potent component for cancer prevention, including liver cancer. Yie et al. explored the probable mechanisms underlying the antiliver cancer action of UA. Taken together, the results demonstrated that UA inhibited proliferation

anism might be closely involved in the MAPK and PKC signaling pathways [25].

tion therapy with AS-IV and curcumin for treatment of liver cancer [26].

effect of WM622 [22].

suppression of PI3K/Akt signaling [24].

cells [23].

116 Liver Cancer

Bilobol is a Chinese medical ingredient. Xu et al. identified that bilobol administration could suppress expansion of HepG2 cells, which pretreated with lipopolysaccharide (LPS) to induce inflammation. Bilobol appeared to exhibit antitumor effect via inhibiting the RhoA/ROCK signal transduction during the anti-inflammatory response [28].

Fucoidan, a sulfated polysaccharide isolated from brown algae, has been applied as an anticancer drug for hundreds of years in Chinese medicine. The results from Zhu et al. revealed that fucoidan had the capacity of antitumor partially through inhibiting the proliferation of HCC cells, although it is unable to repress the angiogenesis induced by HCC [29]. In another study, fucoidan displayed the antimetastatic efficacy on HCC cell lines via upregulating p42/44 MAPK-dependent NDRG-1/CAP43 pathway. Also, fucoidan was found to protect against bile acid-induced hepatocyte apoptosis. This ability suggested fucoidan presented a potent therapeutic agent for HCC treatment [30].

Telekin is a eudesmane-type sesquiterpene lactone extracted from the natural plant Carpesium divaricatum, which presents strong antiproliferative activity in cancer cells. Zheng et al. found that telekin promoted HCC cells apoptosis by activating the mitochondria-mediated apoptotic pathway [31].

Gigantol is a phenolic substance derived from the genus Dendrobium. Chen et al. investigated gigantol efficacy on liver cancer cells and the results suggested gigantol inhibited cells expansion and induced apoptosis in HepG2 cells through PI3K/Akt/NF-kappaB signal transduction [32].

The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play critical roles in the modulation of cell fate. The two factors even could become potent targets and provide support for the development of antineoplastic agents. Celastrol, one of the triterpene compounds derived from herbal medicine, exerts antitumor effects on various malignancies. Ren et al. demonstrated that for HCC cells, exposure to celastrol led to the sensitivity of the intrinsic apoptotic pathway, at least partly through ER stress and the UPR. Moreover, celastrol was found to repress H22 tumor growth in murine syngeneic model studies by inducing ER stress and apoptosis. These data suggested that targeting ER-stress/UPR was an efficient way for celastrol becoming a potent drug for HCC therapy [33]. Cytisine, a quinolizidine alkaloid, also a major bioactive constituent purified from the Sophora alopecuroides L. It was reported to exhibit inhibitory effects in treating liver cancer by inducing the ER stress-mediated apoptotic pathway through activating CHOP, JNK, and caspase-4 signaling pathways in liver cancer cells. This phenomenon suggested a novel target compound potentially to treat liver cancer [34].

RA-XII, a naturally occurring compound originated from Chinese herbal medicine Rubia yunnanensis, possesses activities of anti-inflammatory and antitumor. Song et al. revealed that RA-XII accelerated apoptosis and repressed protective autophagy via signaling pathway AMPK/ mTOR/P70S6K in HepG2 cells, suggesting RA-XII, a cyclopeptide, provides the therapeutic support for potentially being an autophagy inhibitor drug in the therapy of hepatic tumor [35].

There are many bioactive compounds from Chinese medicine, which are also one part of daily diet. For example, Bullacta exarata is widely used as a part of normal diet in Asia, and also it is an agent with liver- and kidney-nourishing functions. One polysaccharide conjugate BEPS-IA was extracted from B. exarata. Liao et al. reported that BEPS-IA exerted a potent inhibition in HepG2 cells growth in a concentration-dependent manner via inducing apoptosis and blocking cell cycle. Furthermore, it was corroborated that this effect was involved in downregulation of Bcl-2, upregulation of p53, p21 and Bax, suggesting that BEPS-IA may be a new dietary drug for HCC obtained from herbals and shed light on getting a deeper understanding on the action mechanisms [36]. Diosgenin is a major bioactive component of Dioscoreaceae plants including yam, which is commonly prescribed in Chinese medicine, and a common vegetable all over the world. Diosgenin remarkably repressed the proliferation of several HCC cell lines in a dosage-dependent manner. Deeper investigation reported the apoptosis and cell cycle G2/M arrest were involved in the inactivation of Akt, activation of the caspase cascades, and upregulation of p21 and p27 expression. These results suggested that diosgenin may serve potentially as a novel antiliver cancer dietary supplement [37]. Armillaria mellea (A. mellea) is a honey mushroom, which is currently often consumed worldwide as a dietary supplement. Armillarikin was purified from A. mellea, which is an important component of Chinese medicine "Tianma." Chen et al. investigated the cytotoxicity of armillarikin against HCC cell lines such as Huh7, HA22T, and HepG2 cells. Armillarikin treatment induced apoptosis that was mediated by ROS and accompanied by the collapse of mitochondrial and activation of caspase-8 and -3 in cancer cells, suggesting the potential of armillarikin serving as an potent antihepatoma drug [38]. Corosolic acid analogue (CAA) is a triterpenoid saponin isolated from Actinidia valvata Dunn (Actinidiaceae), a kind of well-known fruit. The study investigated the antiproliferation and inducing apoptosis effects of CAA in three hepatoma cell lines. The data showed for the first time that CAA inhibited expansion of liver cancer cell lines and induced G1 phase arrest. Moreover, proapoptotic effect of CAA was mediated by the activation of TNF-α, caspases, and mitochondrial pathway [39].

[42]. Another study investigated the mechanism of NCTD-induced apoptosis in HepG2 cells, which indicated that NCTD could reverse the methylation state of RASSF1A gene and recover its expression, providing the theoretical information for further development in clinical application [43]. Also, Zhang et al. found in multiple HCC cell lines that NCTD could induce transcriptional repression of Mcl-1 and significantly enhance ABT-737-triggered cell viability inhibition and

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 119

Bufalin is the major bioactive constituent of the Chinese medicine Chansu, which is presently employed in clinical practice for cancer therapy. A number of groups have investigated the therapy efficacy of bufalin on hepatoma, either in vivo or in vitro, to explore the therapeutic potential of the drug. Qiu et al. reported that bufalin exhibited considerable antitumor activities in liver cancer cell lines HCCLM3 and HepG2 and the underlying mechanism might be related to the repression of signaling pathway AKT/GSK3β/β-catenin/E-cadherin [45]. Tsai et al. demonstrated that bufalin led to autophagic cell death and G2/M cell cycle phase arrest in SK-HEP-1 HCC cells via activating AKT/mTOR signal transduction pathway [46]. Another group reported that bufalin exerted remarkable antiproliferative activity and apoptosis induction in Huh-7 and HepG-2 cancer cells. Further study supported the prosurvival role of bufalin-induced autophagy when the autophagy pathway was retarded with specific chemical inhibitors, indicating a promising therapeutic approach for HCC therapy combining bufalin

In searching for active antihepatoma ingredients from toad venom, which is a frequent prescription applied in HCC treatment, Zhang et al. discovered that arenobufagin, a bufadienolide derived from toad venom, had prominent anticancer capacity against HepG2 cells and the corresponding multidrug-resistant cells, namely HepG2/ADM. They illuminated the molecular mechanisms of arenobufagin, which involved crosstalk between autophagy and apoptosis through PI3K/Akt/mTOR pathway suppression. Consequently, these findings contributed to the development of arenobufagin into a chemotherapeutic agent in liver cancer treatment [48]. Another compound, namely hellebrigenin, which was also isolated from Venenum bufonis, was found to significantly repress HepG2 cell viability and colony formation. Further exploration revealed the cytotoxicity of hellebrigenin in HepG2 cells and underscored the antihepatoma activity of hellebrigenin as an active component of Venenum bufonis. Hellebrigenin induced DNA damage, triggered cell cycle arrest, and subsequently initiated mitochondrial apoptosis. Moreover, Akt was found to take a role in cell cycle and apoptosis modulation induced by hellebrigenin. The findings showed the potential of hellebrigenin used as a chemotherapeutic

2.2. Functional roles of Chinese medicine extracts and fractions in liver cancer

Asparagus is not only consumed in daily diet but also employed as an agent in Chinese medicine for multiple types of malignancies therapy. An extract from asparagus, asparagus polysaccharide, has been confirmed to be the major bioactive constituent of asparagus in the respect of antitumor as well as immunity-enhancing activities. In clinical practice, it has been used in a number of malignancies treatment [50]. Weng et al. applied tumor-bearing rat model to systemically evaluate the toxicity and antitumor activity of asparagus polysaccharide and

apoptosis [44].

with a specific autophagy inhibitor [47].

drug for future HCC clinical application [49].

1,6,7-trihydroxyxanthone (THA) is an active small molecule purified from Goodyera oblongifolia. The compound was discovered to strongly inhibit cancer cell proliferation and induced apoptosis in hepatoma carcinoma cells partially mediated by the repression of Bmi-1 and activation of miR-218 [40].

An active ingredient cordycepin was extracted from "Dong Chong Xia Cao." It has been implicated in regulating multiple physiological actions especially antitumor effects. Yao et al. revealed that cordycepin might contribute to tumor progression, EMT, migration, and invasion inhibition in HCC by suppression of signaling pathways E-cadherin and integrin/FAK. Hence, cordycepin is a supplementary candidate or therapeutic agent for preventing liver tumor expansion [41].

Norcantharidin (NCTD), a small-molecule antitumor drug originated from small animal blister beetle, has been currently applied as a potent antineoplastic agent for several kinds of cancers including HCC. The expression of FAM46C, which has been firstly reported as a tumor suppressor for multiple myeloma, was demonstrated to enhance with NCTD administration. FAM46C, a tumor inhibitor for HCC, was important for proapoptotic effects and antiproliferation of NCTD [42]. Another study investigated the mechanism of NCTD-induced apoptosis in HepG2 cells, which indicated that NCTD could reverse the methylation state of RASSF1A gene and recover its expression, providing the theoretical information for further development in clinical application [43]. Also, Zhang et al. found in multiple HCC cell lines that NCTD could induce transcriptional repression of Mcl-1 and significantly enhance ABT-737-triggered cell viability inhibition and apoptosis [44].

There are many bioactive compounds from Chinese medicine, which are also one part of daily diet. For example, Bullacta exarata is widely used as a part of normal diet in Asia, and also it is an agent with liver- and kidney-nourishing functions. One polysaccharide conjugate BEPS-IA was extracted from B. exarata. Liao et al. reported that BEPS-IA exerted a potent inhibition in HepG2 cells growth in a concentration-dependent manner via inducing apoptosis and blocking cell cycle. Furthermore, it was corroborated that this effect was involved in downregulation of Bcl-2, upregulation of p53, p21 and Bax, suggesting that BEPS-IA may be a new dietary drug for HCC obtained from herbals and shed light on getting a deeper understanding on the action mechanisms [36]. Diosgenin is a major bioactive component of Dioscoreaceae plants including yam, which is commonly prescribed in Chinese medicine, and a common vegetable all over the world. Diosgenin remarkably repressed the proliferation of several HCC cell lines in a dosage-dependent manner. Deeper investigation reported the apoptosis and cell cycle G2/M arrest were involved in the inactivation of Akt, activation of the caspase cascades, and upregulation of p21 and p27 expression. These results suggested that diosgenin may serve potentially as a novel antiliver cancer dietary supplement [37]. Armillaria mellea (A. mellea) is a honey mushroom, which is currently often consumed worldwide as a dietary supplement. Armillarikin was purified from A. mellea, which is an important component of Chinese medicine "Tianma." Chen et al. investigated the cytotoxicity of armillarikin against HCC cell lines such as Huh7, HA22T, and HepG2 cells. Armillarikin treatment induced apoptosis that was mediated by ROS and accompanied by the collapse of mitochondrial and activation of caspase-8 and -3 in cancer cells, suggesting the potential of armillarikin serving as an potent antihepatoma drug [38]. Corosolic acid analogue (CAA) is a triterpenoid saponin isolated from Actinidia valvata Dunn (Actinidiaceae), a kind of well-known fruit. The study investigated the antiproliferation and inducing apoptosis effects of CAA in three hepatoma cell lines. The data showed for the first time that CAA inhibited expansion of liver cancer cell lines and induced G1 phase arrest. Moreover, proapoptotic effect of CAA was mediated by the

activation of TNF-α, caspases, and mitochondrial pathway [39].

tion of miR-218 [40].

118 Liver Cancer

expansion [41].

1,6,7-trihydroxyxanthone (THA) is an active small molecule purified from Goodyera oblongifolia. The compound was discovered to strongly inhibit cancer cell proliferation and induced apoptosis in hepatoma carcinoma cells partially mediated by the repression of Bmi-1 and activa-

An active ingredient cordycepin was extracted from "Dong Chong Xia Cao." It has been implicated in regulating multiple physiological actions especially antitumor effects. Yao et al. revealed that cordycepin might contribute to tumor progression, EMT, migration, and invasion inhibition in HCC by suppression of signaling pathways E-cadherin and integrin/FAK. Hence, cordycepin is a supplementary candidate or therapeutic agent for preventing liver tumor

Norcantharidin (NCTD), a small-molecule antitumor drug originated from small animal blister beetle, has been currently applied as a potent antineoplastic agent for several kinds of cancers including HCC. The expression of FAM46C, which has been firstly reported as a tumor suppressor for multiple myeloma, was demonstrated to enhance with NCTD administration. FAM46C, a tumor inhibitor for HCC, was important for proapoptotic effects and antiproliferation of NCTD Bufalin is the major bioactive constituent of the Chinese medicine Chansu, which is presently employed in clinical practice for cancer therapy. A number of groups have investigated the therapy efficacy of bufalin on hepatoma, either in vivo or in vitro, to explore the therapeutic potential of the drug. Qiu et al. reported that bufalin exhibited considerable antitumor activities in liver cancer cell lines HCCLM3 and HepG2 and the underlying mechanism might be related to the repression of signaling pathway AKT/GSK3β/β-catenin/E-cadherin [45]. Tsai et al. demonstrated that bufalin led to autophagic cell death and G2/M cell cycle phase arrest in SK-HEP-1 HCC cells via activating AKT/mTOR signal transduction pathway [46]. Another group reported that bufalin exerted remarkable antiproliferative activity and apoptosis induction in Huh-7 and HepG-2 cancer cells. Further study supported the prosurvival role of bufalin-induced autophagy when the autophagy pathway was retarded with specific chemical inhibitors, indicating a promising therapeutic approach for HCC therapy combining bufalin with a specific autophagy inhibitor [47].

In searching for active antihepatoma ingredients from toad venom, which is a frequent prescription applied in HCC treatment, Zhang et al. discovered that arenobufagin, a bufadienolide derived from toad venom, had prominent anticancer capacity against HepG2 cells and the corresponding multidrug-resistant cells, namely HepG2/ADM. They illuminated the molecular mechanisms of arenobufagin, which involved crosstalk between autophagy and apoptosis through PI3K/Akt/mTOR pathway suppression. Consequently, these findings contributed to the development of arenobufagin into a chemotherapeutic agent in liver cancer treatment [48]. Another compound, namely hellebrigenin, which was also isolated from Venenum bufonis, was found to significantly repress HepG2 cell viability and colony formation. Further exploration revealed the cytotoxicity of hellebrigenin in HepG2 cells and underscored the antihepatoma activity of hellebrigenin as an active component of Venenum bufonis. Hellebrigenin induced DNA damage, triggered cell cycle arrest, and subsequently initiated mitochondrial apoptosis. Moreover, Akt was found to take a role in cell cycle and apoptosis modulation induced by hellebrigenin. The findings showed the potential of hellebrigenin used as a chemotherapeutic drug for future HCC clinical application [49].

#### 2.2. Functional roles of Chinese medicine extracts and fractions in liver cancer

Asparagus is not only consumed in daily diet but also employed as an agent in Chinese medicine for multiple types of malignancies therapy. An extract from asparagus, asparagus polysaccharide, has been confirmed to be the major bioactive constituent of asparagus in the respect of antitumor as well as immunity-enhancing activities. In clinical practice, it has been used in a number of malignancies treatment [50]. Weng et al. applied tumor-bearing rat model to systemically evaluate the toxicity and antitumor activity of asparagus polysaccharide and asparagus gel-like material. The results showed a certain tumor inhibitory effect of them via promoting cell apoptosis and suppressing tumor angiogenesis when given as transarterial chemoembolization (TACE) therapy. Meanwhile, it exerted the antihepatoma activity with lower toxic effects as well as reduced kidney and liver functional damage, highlighting its chemotherapeutic potential in clinical application for future liver cancer TACE therapy [51].

Salvia chinensis Benth has been traditionally exploited for several centuries since old times to treat malignant diseases including HCC. In a study, total flavonoids isolated from Salvia chinensis Benth were shown to own the capability of inducing HCC cell apoptosis both in vitro and in vivo, which appeared to be implicated in the suppression of NF-κB activity [59]. Coptidis rhizoma has been used in clinical practice for tumor treatment in Chinese medicine, and recent experiments in our laboratory have supported its employment in tumor treatment. Zhu et al. examined the anticancer efficacy of Coptidis rhizoma aqueous extract (CRAE) on HCC cells and found the alterations of miR-21 and miR-23a after treatment with CRAE. The results suggested that CRAE targeted the miRNAs in hepatoma cells [60]. Wang et al. found that CRAE could remarkably downregulate Rho/ROCK signal transduction, then finally interfere MHCC97-L cell migration [61]. As we know, angiogenesis is an important factor, which is beneficial for tumor expansion. Tan et al. confirmed that antiangiogenic effect of CRAE on HCC was partially dependent to an eEF2-driven pathway [62]. All these findings supported the potential application of CRAE

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 121

Prunella vulgaris (PV) is a small tree that has been employed clinically for thousands of years in Asia to treat herpetic keratitis. According to previous researches, it has showed PV could repress TPA-induced activation of MMP-9 and suppress hepatoma cells migration and invasion. Data suggested that by modulating multiple signaling pathways, PV modified the metastatic microenvironment of HCC. PV thus may provide useful information for systemic

Ethyl acetate extract (EAE) of Euphorbia helioscopia L. played a critical role in repressing tumor cell proliferation, apoptosis, invasion, and metastasis in vitro. Meanwhile, Cheng et al. found that change of expression of cyclin D1, Bcl-2, Bax, MMP-9 by EAE may be associated with inhibition of tumor growth, induction apoptosis, and suppression of tumor metastasis and

Some Chinese medicine scholars have indicated that endogenous wind-evil acted as a critical role in tumor metastasis. On the basis of this, the agent of dispelling wind-evil could serve as a suppressor for cancer metastasis and poor prognosis. Yan et al. observed that scorpionmedicated serum could restrain proliferation, induce apoptosis, as well as inhibit the capacity of migration and invasion in vitro. Further experiments in HCC tumor-bearing metastasis mice models showed that water decoction of scorpion blocked tumor growth and metastasis. More importantly, these results suggested that scorpion, as an important wind calming drug, could inhibit the metastasis and invasion of liver cancer cells especially through epithelialmesenchymal transition (EMT) reversal, thereby providing a possible potential approach to

Actinidia chinensis Planch root extract (acRoots) has been shown to inhibit cell proliferation in numerous cancer cells. Hou et al. used acRoots to treat HCC cells and observed the distinct effects of acRoots on cell proliferation, cell cycle arrest, and apoptosis. Furthermore, the mechanism underlying these activities was attributed to LAMB3-mediated proliferation suppression and S-phase cell cycle arrest in HepG2 cells [66]. He et al. studied the mechanism in

in HCC therapy.

therapies of HCC [63].

invasion in HCC xenografts [64].

preventing HCC metastasis [65].

Ganoderma lucidum polysaccharides (GLPS) have been exploited as folk Chinese medicine for their properties of immunomodulation and tumor prevention [52]. Li et al. measured the efficacy of GLPS on liver cancer cells in hepatoma-bearing mice model and effectively suppressed the tumor growth. The possible molecular mechanism may be related with an augment of the ratio of regulatory T cell (Treg) to effector T cell (Teff), which is caused by the augment of miR-125b, a predicative marker of poor prognosis and aggressiveness of liver cancer [53].

In China, Trametes robiniophila Murr (Huaier) has recently been used as Chinese medicine in China. It has a great clinical effect as adjuvant therapies in the treatment of HCC. Shan et al. investigated the functions of Huaier on HCC cells and confirmed that HCC growth could be restrained by Huaier through downregulation of yes-associated protein 1 (YAP1) [54].

Ampelopsis sinica root (ASR) is a well-known hepatoprotective Chinese medicine. Wang et al. explored whether ethyl acetate extract from ASRE had the antihepatoma activity both in vitro and in vivo. The findings showed that ASRE had prominent antihepatoma activity, which possibly involved the decreased regulation of inflammatory cytokines such as cyclooxygenase-2, 5-lipoxygenase and FLAP, augment of p53 protein expression and the ratio of bax/bcl-2, caspase-3 activation, as well as survivin repression. Moreover, ASR was found to be nontoxic on normal cells, suggesting that it may serve as a potential therapeutic agent for HCC treatment [55].

An extract of Stellerachamaejasme L. (ESC) had been confirmed as a potential antitumor extract of Chinese medicine. Liu et al. tested that the suppressive effects of ESC on propagation and epithelial mesenchymal transition (EMT) in liver cancer cells were associated with miR-107. The findings indicated ESC retarded HCC expansion and metastasis by regulating the expression of microRNAs and their according target genes [56].

Cnidium monnieri (L.) Cusson (CME) is a frequently used Chinese herbal medicine that treats gynecological diseases and carbuncles. A recent study showed the cell cycle alteration and apoptosis of HepG2 (wildtype p53) and Hep3B (p53null) by ethanol extract of CME, suggesting that CME induced G1 arrest and apoptosis via the Akt/GSK3β signaling pathway [57].

Astragalus membranaceus and Salvia miltiorrhiza are medical plants that have been applied for thousands of years in the treatment of liver diseases. According to previous researches, it has showed that these two herbs and their extracts own the ability to inhibit the development liver cancer. Rui et al. investigated that the compound astragalus and salvia miltiorrhiza extract (CASE) could repress diethylinitrosamine-induced hepatoma in rat model via the inhibition of fibrosis and PAI-1 mRNA transcription, indicating the possibility of being development as antihepatoma agents in preventing and treating human liver cancer [58].

Salvia chinensis Benth has been traditionally exploited for several centuries since old times to treat malignant diseases including HCC. In a study, total flavonoids isolated from Salvia chinensis Benth were shown to own the capability of inducing HCC cell apoptosis both in vitro and in vivo, which appeared to be implicated in the suppression of NF-κB activity [59]. Coptidis rhizoma has been used in clinical practice for tumor treatment in Chinese medicine, and recent experiments in our laboratory have supported its employment in tumor treatment. Zhu et al. examined the anticancer efficacy of Coptidis rhizoma aqueous extract (CRAE) on HCC cells and found the alterations of miR-21 and miR-23a after treatment with CRAE. The results suggested that CRAE targeted the miRNAs in hepatoma cells [60]. Wang et al. found that CRAE could remarkably downregulate Rho/ROCK signal transduction, then finally interfere MHCC97-L cell migration [61]. As we know, angiogenesis is an important factor, which is beneficial for tumor expansion. Tan et al. confirmed that antiangiogenic effect of CRAE on HCC was partially dependent to an eEF2-driven pathway [62]. All these findings supported the potential application of CRAE in HCC therapy.

asparagus gel-like material. The results showed a certain tumor inhibitory effect of them via promoting cell apoptosis and suppressing tumor angiogenesis when given as transarterial chemoembolization (TACE) therapy. Meanwhile, it exerted the antihepatoma activity with lower toxic effects as well as reduced kidney and liver functional damage, highlighting its chemotherapeutic potential in clinical application for future liver cancer TACE therapy [51].

Ganoderma lucidum polysaccharides (GLPS) have been exploited as folk Chinese medicine for their properties of immunomodulation and tumor prevention [52]. Li et al. measured the efficacy of GLPS on liver cancer cells in hepatoma-bearing mice model and effectively suppressed the tumor growth. The possible molecular mechanism may be related with an augment of the ratio of regulatory T cell (Treg) to effector T cell (Teff), which is caused by the augment of miR-125b, a predicative marker of poor prognosis and aggressiveness of liver

In China, Trametes robiniophila Murr (Huaier) has recently been used as Chinese medicine in China. It has a great clinical effect as adjuvant therapies in the treatment of HCC. Shan et al. investigated the functions of Huaier on HCC cells and confirmed that HCC growth could be

Ampelopsis sinica root (ASR) is a well-known hepatoprotective Chinese medicine. Wang et al. explored whether ethyl acetate extract from ASRE had the antihepatoma activity both in vitro and in vivo. The findings showed that ASRE had prominent antihepatoma activity, which possibly involved the decreased regulation of inflammatory cytokines such as cyclooxygenase-2, 5-lipoxygenase and FLAP, augment of p53 protein expression and the ratio of bax/bcl-2, caspase-3 activation, as well as survivin repression. Moreover, ASR was found to be nontoxic on normal cells, suggesting that it may serve as a potential therapeutic agent for HCC treatment [55].

An extract of Stellerachamaejasme L. (ESC) had been confirmed as a potential antitumor extract of Chinese medicine. Liu et al. tested that the suppressive effects of ESC on propagation and epithelial mesenchymal transition (EMT) in liver cancer cells were associated with miR-107. The findings indicated ESC retarded HCC expansion and metastasis by regulating the expres-

Cnidium monnieri (L.) Cusson (CME) is a frequently used Chinese herbal medicine that treats gynecological diseases and carbuncles. A recent study showed the cell cycle alteration and apoptosis of HepG2 (wildtype p53) and Hep3B (p53null) by ethanol extract of CME, suggesting that CME induced G1 arrest and apoptosis via the Akt/GSK3β signaling

Astragalus membranaceus and Salvia miltiorrhiza are medical plants that have been applied for thousands of years in the treatment of liver diseases. According to previous researches, it has showed that these two herbs and their extracts own the ability to inhibit the development liver cancer. Rui et al. investigated that the compound astragalus and salvia miltiorrhiza extract (CASE) could repress diethylinitrosamine-induced hepatoma in rat model via the inhibition of fibrosis and PAI-1 mRNA transcription, indicating the possibility of being devel-

opment as antihepatoma agents in preventing and treating human liver cancer [58].

sion of microRNAs and their according target genes [56].

restrained by Huaier through downregulation of yes-associated protein 1 (YAP1) [54].

cancer [53].

120 Liver Cancer

pathway [57].

Prunella vulgaris (PV) is a small tree that has been employed clinically for thousands of years in Asia to treat herpetic keratitis. According to previous researches, it has showed PV could repress TPA-induced activation of MMP-9 and suppress hepatoma cells migration and invasion. Data suggested that by modulating multiple signaling pathways, PV modified the metastatic microenvironment of HCC. PV thus may provide useful information for systemic therapies of HCC [63].

Ethyl acetate extract (EAE) of Euphorbia helioscopia L. played a critical role in repressing tumor cell proliferation, apoptosis, invasion, and metastasis in vitro. Meanwhile, Cheng et al. found that change of expression of cyclin D1, Bcl-2, Bax, MMP-9 by EAE may be associated with inhibition of tumor growth, induction apoptosis, and suppression of tumor metastasis and invasion in HCC xenografts [64].

Some Chinese medicine scholars have indicated that endogenous wind-evil acted as a critical role in tumor metastasis. On the basis of this, the agent of dispelling wind-evil could serve as a suppressor for cancer metastasis and poor prognosis. Yan et al. observed that scorpionmedicated serum could restrain proliferation, induce apoptosis, as well as inhibit the capacity of migration and invasion in vitro. Further experiments in HCC tumor-bearing metastasis mice models showed that water decoction of scorpion blocked tumor growth and metastasis. More importantly, these results suggested that scorpion, as an important wind calming drug, could inhibit the metastasis and invasion of liver cancer cells especially through epithelialmesenchymal transition (EMT) reversal, thereby providing a possible potential approach to preventing HCC metastasis [65].

Actinidia chinensis Planch root extract (acRoots) has been shown to inhibit cell proliferation in numerous cancer cells. Hou et al. used acRoots to treat HCC cells and observed the distinct effects of acRoots on cell proliferation, cell cycle arrest, and apoptosis. Furthermore, the mechanism underlying these activities was attributed to LAMB3-mediated proliferation suppression and S-phase cell cycle arrest in HepG2 cells [66]. He et al. studied the mechanism in the extent of metabolic alterations. The data showed that acRoots could remarkably inhibit cholesterol metabolism through a PCSK9-mediated signaling pathway, which in turn limited the nutrients production that was essential for the proliferation of cancer cells [67].

Sini-San (SNS) has been employed for the treatment of various types of liver disease. This formulation comprises four prescriptions of Chinese herbal medicine and was first described in "Shanghan Lun (Treatise on Cold Damage Disorders or the Treatise on Cold Injury)," established by one of the most famous ancient Chinese physicians, Zhang Zhongjing (150– 219 AD). SNS has shown significant inhibition on tumor growth in HepG2 xenograft model. Lin et al. elucidated the molecular mechanism by which SNS exerted an antimigratory and anti-invasive effect on HBx-activated liver cancer cells. These results showed that SNS suppressed invasiveness and metastasis in HCC cells via multiple signal transduction pathways including downregulating PI3K/Akt, decreasing MAPK and IκB signaling, inhibiting NF-κB and AP-1 activity, and reducing MMP-9 expression. Thus, SNS might be helpful to

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 123

Songyou Yin (SYY), a composite formula, showed efficacy to repress tumor proliferation, metastasis, and recurrence. An interesting study explored that SYY combining with moderate swimming has potent effect on retraining tumor growth and metastasis mainly via enhancing

Niu-Huang-Shen (NHS) has been accepted and used in China for a long time with its various effects such as antipyretic, anti-inflammatory, and vasodilatation effects. It was showed that NHS inhibited cell cycle arrest, induced cell apoptosis, and then repressed cell proliferation and invasion, probably through the significant suppression of Yes-associated protein (YAP) expression. NHS may have the therapeutic potential for treating HCC more effectively [77].

Shuihonghuazi formula (SHHZF) has been employed for early stage of liver cancer in clinical therapy for a long time; a study was designed to investigate potent effects of SHHZF on hepatoma and its metabolomic profiles. The results elucidated that SHHZF exerted inhibitory effects against liver cancer by adjusting the activities of PE N-methyl transferase, lysophospholipase D, methyle-

Chinese medicine is appreciated for its 5000-year-old history and still holds a prominent position in primary health care in China. Chinese medicine could complement Western medicine by using modern techniques; thus, increasing interests in Chinese medicine has been observed over the Western world. In Chinese medicine, a wide range of ingredients have been proven to achieve various effects in cancer therapy, including alleviating the toxicity to human body, retraining tumor metastasis and recurrence, enhancing chemo- or radio-therapeutic effects, and

Long-term food restriction and diarrhea may be an adverse factor for liver cancer. Jian-pi-jiedu decoction (JPJD) could improve the quality of life of hepatoma subjects, in particular, the symptoms of diarrhea and decreased food intake. A research indicated JPJD could improve the condition of tumor-bearing rats, which were pretreated with diarrhea and food restriction by increasing ABCC2 expressional level and downregulating the OATP1B2 in liver normal tissues

3. Chinese medicine as a complementary treatment of liver cancer

subsequent improving the general status of patients and extending their survival time.

while downregulating ABCC2 as well as upregulating OATP1B2 in cancer tissues [79].

interfere the invasion and metastasis of HCC [75].

netetrahydrofolate reductase, and lysophospholipase [78].

immune function [76].

Ethanol extract of root of Prunus persica, which is an important ingredient in Chinese medicine prescription, exhibited antitumor effect in liver cancer. Scholars recently reported that Prunus persica could repress cell growth in a time and dose-dependent fashion, causing sustained M/ G2 phase arrest as well as notably suppressing the migration of HepG2 cells and the expression of extracellular matrix metalloproteases, MMP3 and MMP9 [68].

Realgar (As4S4), one of the most useful mineral drugs in Chinese medicine, has been employed in clinical therapy as a potential agent for cancer therapy. However, due to its low solubility and subsequent poor bioavailability, it is difficult to achieve the effective blood medicine dose unless with high dosage of realgar and long period of treatment. A recent study explored realgar transforming solution (RTS) and found the strong antihepatoma activity of RTS via inducing ROS [69].

#### 2.3. The role of Chinese medicine composite formulae in regressing liver cancer

Huang-lian-jie-du-tang (HLJDT) is oriental medicinal formulation known to possess antiinflammatory activity. The prescription has been well documented for thousands of years and used for liver protection in Asian community [70]. Recent researches have postulated HLJDT as a regimen for cancer treatment, particularly hepatoma. Hsu et al. found that HLJDT might have an effect on human liver cancer cell lines, Hep G2 and PLC/PRF/5. The results showed that HLJDT significantly triggered cell cycle arrest and contributed to the mitochondrial apoptotic pathway by reducing the level and activity of NF-κB, which suggested that HLJDT might be a promising chemotherapeutic agent without causing cytotoxicity to normal cellular environment [71]. Wang et al. examined the suppressive efficacy of HLJDT on the liver cancer expansion and found that involvement of eEF2 inhibition might be the key mechanism mediating the inhibitory effect of the formula [72].

Yiguanjian (YGJ), a classic liver-YIN tonifying herbal formula, was established by ancient Chinese medicine practitioner Wei Zhixian in the Qing Dynasty (AD 1722–1772). Researchers optimized the prescription of YGJ on the basis of modern principles in clinical practice of Chinese medicine and then evaluated the antitumor activity of modified YGJ (MYGJ) on Bel-7402 human liver cancer cells. These data showed that MYGJ could interfere proliferation suspension and induce anoikis in cancer cells. The mechanisms underlying the actions of MYGJ might involve in inhibiting the phosphorylation and expression of p38 MAPK, and subsequent regulating intrinsic and extrinsic pathways of apoptosis [73].

Pien Tze Huang (PZH) is an extensively employed prescription in the treatment of multiple malignancies and has possible therapeutic effects in clinical therapy for HCC. Qi et al. aimed to elucidate the efficacy of PZH on the proliferation and apoptosis of liver cancer cell lines and demonstrated PZH could effectively inhibit cancer cell proliferation and induce apoptosis in Bel-7402 HCC cells by upregulating miR-16, which has been verified as tumor suppressor, suggesting a novel potential therapeutic for HCC patients [74].

Sini-San (SNS) has been employed for the treatment of various types of liver disease. This formulation comprises four prescriptions of Chinese herbal medicine and was first described in "Shanghan Lun (Treatise on Cold Damage Disorders or the Treatise on Cold Injury)," established by one of the most famous ancient Chinese physicians, Zhang Zhongjing (150– 219 AD). SNS has shown significant inhibition on tumor growth in HepG2 xenograft model. Lin et al. elucidated the molecular mechanism by which SNS exerted an antimigratory and anti-invasive effect on HBx-activated liver cancer cells. These results showed that SNS suppressed invasiveness and metastasis in HCC cells via multiple signal transduction pathways including downregulating PI3K/Akt, decreasing MAPK and IκB signaling, inhibiting NF-κB and AP-1 activity, and reducing MMP-9 expression. Thus, SNS might be helpful to interfere the invasion and metastasis of HCC [75].

the extent of metabolic alterations. The data showed that acRoots could remarkably inhibit cholesterol metabolism through a PCSK9-mediated signaling pathway, which in turn limited

Ethanol extract of root of Prunus persica, which is an important ingredient in Chinese medicine prescription, exhibited antitumor effect in liver cancer. Scholars recently reported that Prunus persica could repress cell growth in a time and dose-dependent fashion, causing sustained M/ G2 phase arrest as well as notably suppressing the migration of HepG2 cells and the expres-

Realgar (As4S4), one of the most useful mineral drugs in Chinese medicine, has been employed in clinical therapy as a potential agent for cancer therapy. However, due to its low solubility and subsequent poor bioavailability, it is difficult to achieve the effective blood medicine dose unless with high dosage of realgar and long period of treatment. A recent study explored realgar transforming solution (RTS) and found the strong antihepatoma activity of RTS via inducing

Huang-lian-jie-du-tang (HLJDT) is oriental medicinal formulation known to possess antiinflammatory activity. The prescription has been well documented for thousands of years and used for liver protection in Asian community [70]. Recent researches have postulated HLJDT as a regimen for cancer treatment, particularly hepatoma. Hsu et al. found that HLJDT might have an effect on human liver cancer cell lines, Hep G2 and PLC/PRF/5. The results showed that HLJDT significantly triggered cell cycle arrest and contributed to the mitochondrial apoptotic pathway by reducing the level and activity of NF-κB, which suggested that HLJDT might be a promising chemotherapeutic agent without causing cytotoxicity to normal cellular environment [71]. Wang et al. examined the suppressive efficacy of HLJDT on the liver cancer expansion and found that involvement of eEF2 inhibition might be the key mechanism medi-

Yiguanjian (YGJ), a classic liver-YIN tonifying herbal formula, was established by ancient Chinese medicine practitioner Wei Zhixian in the Qing Dynasty (AD 1722–1772). Researchers optimized the prescription of YGJ on the basis of modern principles in clinical practice of Chinese medicine and then evaluated the antitumor activity of modified YGJ (MYGJ) on Bel-7402 human liver cancer cells. These data showed that MYGJ could interfere proliferation suspension and induce anoikis in cancer cells. The mechanisms underlying the actions of MYGJ might involve in inhibiting the phosphorylation and expression of p38 MAPK, and

Pien Tze Huang (PZH) is an extensively employed prescription in the treatment of multiple malignancies and has possible therapeutic effects in clinical therapy for HCC. Qi et al. aimed to elucidate the efficacy of PZH on the proliferation and apoptosis of liver cancer cell lines and demonstrated PZH could effectively inhibit cancer cell proliferation and induce apoptosis in Bel-7402 HCC cells by upregulating miR-16, which has been verified as tumor suppressor,

subsequent regulating intrinsic and extrinsic pathways of apoptosis [73].

suggesting a novel potential therapeutic for HCC patients [74].

the nutrients production that was essential for the proliferation of cancer cells [67].

2.3. The role of Chinese medicine composite formulae in regressing liver cancer

sion of extracellular matrix metalloproteases, MMP3 and MMP9 [68].

ating the inhibitory effect of the formula [72].

ROS [69].

122 Liver Cancer

Songyou Yin (SYY), a composite formula, showed efficacy to repress tumor proliferation, metastasis, and recurrence. An interesting study explored that SYY combining with moderate swimming has potent effect on retraining tumor growth and metastasis mainly via enhancing immune function [76].

Niu-Huang-Shen (NHS) has been accepted and used in China for a long time with its various effects such as antipyretic, anti-inflammatory, and vasodilatation effects. It was showed that NHS inhibited cell cycle arrest, induced cell apoptosis, and then repressed cell proliferation and invasion, probably through the significant suppression of Yes-associated protein (YAP) expression. NHS may have the therapeutic potential for treating HCC more effectively [77].

Shuihonghuazi formula (SHHZF) has been employed for early stage of liver cancer in clinical therapy for a long time; a study was designed to investigate potent effects of SHHZF on hepatoma and its metabolomic profiles. The results elucidated that SHHZF exerted inhibitory effects against liver cancer by adjusting the activities of PE N-methyl transferase, lysophospholipase D, methylenetetrahydrofolate reductase, and lysophospholipase [78].
