3. Chinese medicine as a complementary treatment of liver cancer

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

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

In terms of radioprotective and radiosensitizing functions of Chinese medicine, a series of concerning studies have been conducted. Numerous Chinese medicine agents have been confirmed to strengthen the therapeutic gain of radiotherapy by the way of serving as radioprotectors for healthy cells or as radiosensitizers for cancer cells [80, 81]. Botanical agents are comprised of multiple phytochemical compounds that may work synergistically or even individually, not only exhibiting favorable therapeutic effects, but also with safety profiles and lower toxicity [82].

synergistic effects may be associated with apoptosis and 5-FU metabolism, as evidenced by the increased bax/bcl-2 ratios, upregulated p53 expressions, and induced PARP cleavage [88].

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 125

ADCX, a natural cycloartane triterpenoid isolated from Cimicifugae rhizome, impaired autophagic degradation by inhibiting lysosomal cathepsin B expression in multidrug resistant cell line, namely HepG2/ADM, which consequently lead to apoptosis, suggesting that an active constituent from Cimicifugae rhizome could overcome multidrug resistance in hepatoma cells by the role of persistent Akt activation in inhibition of autophagic degradation [89]. Arsenic trioxide (As2O3) with high doses is employed to treat solid tumors and acute promyelocytic leukemia, which mostly induce toxic side effects to healthy cells. Andrographolide is a kind of Chinese medicine that exhibits various effects against diseases such as antiinflammatory, antivirus, antitumor, and so on. Duan et al. demonstrated that andrographolide enhanced As2O3-induced apoptosis in a caspase-3-dependent manner via downregulation of EphB4 in HCC cells. These findings suggested that lower concentrations of As2O3 in combination with andrographolide could be used as chemotherapy for HCC with the potential to minimize the

The aqueous extract of Solanum nigrum (AE-SN) is an important constituent in some Chinese medicine formulae used in the treatment of cancer. Wang et al. explored the antitumor effect of AE-SN in combination with a normal chemotherapeutic drug, namely doxorubicin or cisplatin, in HCC cell lines Hep3B and HepJ5. The results indicated the integrated treatment with AE-SN-potentiated doxorubicin and cisplatin-induced cytotoxicity through the cleavage of caspase-7 and accumulation of microtubule-associated protein-1 light chain-3 A/1B II (LC-3 A/B II), which were involved in autophagic and apoptotic cell death, respectively. Thereby, this combinatorial strategy of AE-SN and cisplatin or doxorubicin may be exploited to be a candi-

A recent research was performed to explore the combination effect of Huaier aqueous extract and chemotherapeutic agent cisplatin or rapamycin. The findings showed that Huaier had the capacity of activating mTOR signaling, which contributed to the enhanced cancer cells sensitivity to chemotherapeutics in response to Huaier administration. Huaier, thus, can potentially be used in integrated chemotherapy with rapamycin or cisplatin for liver cancer therapy [92]. Cinobufacini, a mixture of a number of components in Chinese medicine, has been used extensively for HCC therapy with strong apoptosis-inducing activity. Xia et al. used a combination of doxorubicin with cinobufacini to achieve tumor-suppression efficiency and found the combination group had a more considerable apoptotic effect by affecting proteins and RNA of apoptosisrelated elements, such as Bcl-2, Bax, Bid, and cytochrome C. Consequently, cinobufacini in combination with chemotherapeutic agents might be a new strategy to improve the treatment

Shufeng Jiedu Capsule (SFJDC) has been widely used due to its various pharmacological actions such as anti-inflammation, antibacterial, antiviral, and antitumor. Recently, scholars used combination of SFJDC with doxorubicin to treat liver cancer cells and further explored the underlying mechanisms of SFJDC as well as its constituents in vitro. The data showed that the combination group induced more considerable apoptosis and invasion and migration suppression than control group by targeting NF-κB, Akt/mTOR, and mitochondrial signaling pathways [94].

adverse events from As2O3 treatment alone [90].

date regimen to treat HCC patients [91].

effect for HCC patients [93].

Ganoderma lucidum polysaccharide (GLP) is well known for its various pharmacologic properties including antitumor effects [52]. A study recently demonstrated that GLP treatment may augment growth inhibition and apoptotic death of HepG2 cells, which induced by radiation, and revealed the regulatory role of Akt signaling pathway for GLP-mediated radiosensitivity in HCC cells exposed to radiation [83].

Kou et al. investigated the radiosensitizing effects of ultrafiltration extract of Radix Angelicae Sinensis-Radix Hedysari (RAS-RH) in human hepatoma cells. The results reported that the RAS-RH significantly enhanced the radiosensitivity of H22 cells of 12C6+ heavy ion radiation. Further study explored the underlying mechanism of radiosensitization, which is to increase caspase-dependent apoptosis via reducing surviving expressional level, suggesting a promising potent radiosensitizer [84].

Zhang et al. demonstrated that a flavonoid dihydromyricetin (DHM) exerted anticancer activity against hepatoma cells as well as xenotransplanted tumors in nude mice by activating the p53-dependent apoptosis pathway. And best of all, DHM was indicated to play a prominent role when administered in combination with cisplatin [85]. In this case, DHM could be an ideal anticancer drug with minimal side effects because it can alleviate cytotoxicity caused by cisplatin in normal liver cells.

Some studies investigated the adjunctive role of bufalin in reversal chemoresistance in the treatment of liver cancer. The Akt activation triggered by sorafenib is regarded to be responsible for this resistant phenomenon. Zhai et al. investigated that bufalin had the ability of reversing both inherent and acquired resistance to sorafenib via the IRE1 pathway in an ERstress-dependent manner. These data warranted further studies to examine the utility of bufalin in combination with sorafenib as a first- or second-line treatment after sorafenib alone gains failure in advanced liver cancer [86]. Fluorouracil (5-FU) is a type of anticancer chemotherapeutics, which has been used for 40 years in clinical practice. A research confirmed the reversal effect of bufalin on drug resistance in a moderate multidrug resistance cell line Bel-7402/5-FU. They found Bufalin could block the cell cycle at G0/G1 phase, induce apoptosis through an increase of Bax/Bcl-xL ratio, inhibit the drug efflux pump activity via downregulation of MRP1, and reduce the expression of thymidylate synthase in vitro. All these data revealed that in Bel-7402/5-FU cells, the combination of bufalin with cytotoxic drugs could considerably reverse the MDR through multiple pathways including cell cycle arrest, apoptosis induction, etc., indicating an effective strategy for the chemotherapy of HCC [87].

Xu et al. investigated the efficacy of drug combination of luteolin and 5-FU on the proliferation of HepG2 and Bel-7402 cells. The data showed that luteolin synergized 5-FU at different dose ratios and then exerted the antitumor effects against HCC cells. Potential mechanism for synergistic effects may be associated with apoptosis and 5-FU metabolism, as evidenced by the increased bax/bcl-2 ratios, upregulated p53 expressions, and induced PARP cleavage [88].

In terms of radioprotective and radiosensitizing functions of Chinese medicine, a series of concerning studies have been conducted. Numerous Chinese medicine agents have been confirmed to strengthen the therapeutic gain of radiotherapy by the way of serving as radioprotectors for healthy cells or as radiosensitizers for cancer cells [80, 81]. Botanical agents are comprised of multiple phytochemical compounds that may work synergistically or even individually, not only exhibiting favorable therapeutic effects, but also with safety profiles

Ganoderma lucidum polysaccharide (GLP) is well known for its various pharmacologic properties including antitumor effects [52]. A study recently demonstrated that GLP treatment may augment growth inhibition and apoptotic death of HepG2 cells, which induced by radiation, and revealed the regulatory role of Akt signaling pathway for GLP-mediated radiosensitivity

Kou et al. investigated the radiosensitizing effects of ultrafiltration extract of Radix Angelicae Sinensis-Radix Hedysari (RAS-RH) in human hepatoma cells. The results reported that the RAS-RH significantly enhanced the radiosensitivity of H22 cells of 12C6+ heavy ion radiation. Further study explored the underlying mechanism of radiosensitization, which is to increase caspase-dependent apoptosis via reducing surviving expressional level, suggesting a promis-

Zhang et al. demonstrated that a flavonoid dihydromyricetin (DHM) exerted anticancer activity against hepatoma cells as well as xenotransplanted tumors in nude mice by activating the p53-dependent apoptosis pathway. And best of all, DHM was indicated to play a prominent role when administered in combination with cisplatin [85]. In this case, DHM could be an ideal anticancer drug with minimal side effects because it can alleviate cytotoxicity caused by

Some studies investigated the adjunctive role of bufalin in reversal chemoresistance in the treatment of liver cancer. The Akt activation triggered by sorafenib is regarded to be responsible for this resistant phenomenon. Zhai et al. investigated that bufalin had the ability of reversing both inherent and acquired resistance to sorafenib via the IRE1 pathway in an ERstress-dependent manner. These data warranted further studies to examine the utility of bufalin in combination with sorafenib as a first- or second-line treatment after sorafenib alone gains failure in advanced liver cancer [86]. Fluorouracil (5-FU) is a type of anticancer chemotherapeutics, which has been used for 40 years in clinical practice. A research confirmed the reversal effect of bufalin on drug resistance in a moderate multidrug resistance cell line Bel-7402/5-FU. They found Bufalin could block the cell cycle at G0/G1 phase, induce apoptosis through an increase of Bax/Bcl-xL ratio, inhibit the drug efflux pump activity via downregulation of MRP1, and reduce the expression of thymidylate synthase in vitro. All these data revealed that in Bel-7402/5-FU cells, the combination of bufalin with cytotoxic drugs could considerably reverse the MDR through multiple pathways including cell cycle arrest, apoptosis induction, etc., indicating an effective strategy for the chemotherapy of HCC [87].

Xu et al. investigated the efficacy of drug combination of luteolin and 5-FU on the proliferation of HepG2 and Bel-7402 cells. The data showed that luteolin synergized 5-FU at different dose ratios and then exerted the antitumor effects against HCC cells. Potential mechanism for

and lower toxicity [82].

124 Liver Cancer

in HCC cells exposed to radiation [83].

ing potent radiosensitizer [84].

cisplatin in normal liver cells.

ADCX, a natural cycloartane triterpenoid isolated from Cimicifugae rhizome, impaired autophagic degradation by inhibiting lysosomal cathepsin B expression in multidrug resistant cell line, namely HepG2/ADM, which consequently lead to apoptosis, suggesting that an active constituent from Cimicifugae rhizome could overcome multidrug resistance in hepatoma cells by the role of persistent Akt activation in inhibition of autophagic degradation [89].

Arsenic trioxide (As2O3) with high doses is employed to treat solid tumors and acute promyelocytic leukemia, which mostly induce toxic side effects to healthy cells. Andrographolide is a kind of Chinese medicine that exhibits various effects against diseases such as antiinflammatory, antivirus, antitumor, and so on. Duan et al. demonstrated that andrographolide enhanced As2O3-induced apoptosis in a caspase-3-dependent manner via downregulation of EphB4 in HCC cells. These findings suggested that lower concentrations of As2O3 in combination with andrographolide could be used as chemotherapy for HCC with the potential to minimize the adverse events from As2O3 treatment alone [90].

The aqueous extract of Solanum nigrum (AE-SN) is an important constituent in some Chinese medicine formulae used in the treatment of cancer. Wang et al. explored the antitumor effect of AE-SN in combination with a normal chemotherapeutic drug, namely doxorubicin or cisplatin, in HCC cell lines Hep3B and HepJ5. The results indicated the integrated treatment with AE-SN-potentiated doxorubicin and cisplatin-induced cytotoxicity through the cleavage of caspase-7 and accumulation of microtubule-associated protein-1 light chain-3 A/1B II (LC-3 A/B II), which were involved in autophagic and apoptotic cell death, respectively. Thereby, this combinatorial strategy of AE-SN and cisplatin or doxorubicin may be exploited to be a candidate regimen to treat HCC patients [91].

A recent research was performed to explore the combination effect of Huaier aqueous extract and chemotherapeutic agent cisplatin or rapamycin. The findings showed that Huaier had the capacity of activating mTOR signaling, which contributed to the enhanced cancer cells sensitivity to chemotherapeutics in response to Huaier administration. Huaier, thus, can potentially be used in integrated chemotherapy with rapamycin or cisplatin for liver cancer therapy [92].

Cinobufacini, a mixture of a number of components in Chinese medicine, has been used extensively for HCC therapy with strong apoptosis-inducing activity. Xia et al. used a combination of doxorubicin with cinobufacini to achieve tumor-suppression efficiency and found the combination group had a more considerable apoptotic effect by affecting proteins and RNA of apoptosisrelated elements, such as Bcl-2, Bax, Bid, and cytochrome C. Consequently, cinobufacini in combination with chemotherapeutic agents might be a new strategy to improve the treatment effect for HCC patients [93].

Shufeng Jiedu Capsule (SFJDC) has been widely used due to its various pharmacological actions such as anti-inflammation, antibacterial, antiviral, and antitumor. Recently, scholars used combination of SFJDC with doxorubicin to treat liver cancer cells and further explored the underlying mechanisms of SFJDC as well as its constituents in vitro. The data showed that the combination group induced more considerable apoptosis and invasion and migration suppression than control group by targeting NF-κB, Akt/mTOR, and mitochondrial signaling pathways [94].

Dahuang zhechong pill (DHZCP) is one of the most famous prescriptions from an ancient Chinese medical classic "Jin Kui Yao Lue (Essential Prescriptions from the Golden Cabinet)." DHZCP is officially recorded in the Chinese Pharmacopeia and is commonly used for clinical practice of hepatoma. Wu et al. found that inhibitory growth of doxorubicin-resistant HCC subcutaneous xenografts in nude mice was achieved by DHZCP, and apoptosis promotion was accelerated by doxorubicin. The reversal of doxorubicin resistance by DHZCP was related with energy metabolism decline and regulation of proapoptotic proteins expression [95].

5. Conclusion

the future.

Chinese medicine is increasingly emerging as a novel curative choice for liver cancer. This retrospective review systemically introduced and evaluated the functional roles of Chinese medicine in treating liver cancer. Chinese medicine has potentially exerted efficient anticancer properties. For example, liver cancer progression can be repressed by active constituents derived from Chinese medicine through multiple pathways. The specific network with regard to the potential therapeutic targets for liver cancer treatment was constructed (Figure 1). The detailed relationships between biological factors and refined extracts could be directly visualized in Figure 1. Moreover, composite formulae as promising curative are increasingly indispensable in current clinical practice. As summarized in Table 1, formulae potentially employed in practice were studied in laboratory and the regulatory mechanisms for the treatment of liver cancer have been showed clearly. Also, Chinese medicine may serve as adjuvant agents in surgery as well as in combination with conventional radio- and chemotherapy, to decrease the adverse events or enhance the treatment outcome. Taken all together, Chinese medicine possesses the potential in liver cancer treatment, and rational application in clinical therapy needs to be warranted in

What Chinese Medicine Can Do for Liver Cancer? http://dx.doi.org/10.5772/intechopen.80061 127

Figure 1. Target identification of Chinese medicine-derived compounds and extracts for liver cancer. Literature mining in PubMed with "Chinese Medicine" integrated with "liver cancer" was performed. All filtered data during the last 5 years were imported into a professional software Cytoscape for the establishment of the analysis of network pharmacology. The

top five influential molecules including Akt, Bax, Bcl-2, mTOR, and PI3K could be figured out.
