**4.3. Chinese medicines and their active compounds for averting the invasion and metastasis of liver cancer cells**

Ardipusilloside I is a triterpene‐saponin separated from the TCM herbs *Ardisia pusilla* A. DC. Recent studies have revealed its anticancer effects through inhibition invasion and metastasis of HCC cells [38]. Both *in vitro* and *in vivo* studies demonstrated that Ardipusilloside I may suppress migration of HCC cells partially by decreasing the expression of the metalloprotei‐ nase (MMP)‐2 and MMP‐9 proteins. In addition, Ardipusilloside I can activate Rac1 protein and further induce E‐cadherin which may result in inhibition of cancer cells migration.

As we have discussed earlier, GSPP and its monomeric protein gepsin are effective in inhibiting the proliferation of HCC cells. Recent studies found that GSPP was also effective in suppressing the migration of HCC cells [33]. GSPP treatment remarkably decreased the concentration of intracellular calcium. Many studies have demonstrated that low intracellular calcium concen‐ tration is associated with reduced cancer migration. GSPP treatment could remarkably decrease the concentration of intracellular calcium. Thus, the antimigration effect by GSPP may be partially a consequence of downregulation of intracellular calcium concentration together with an upregulation of actin filaments polymerization in HCC cells.

The hepatic protective effects of Radix Salviae have been verified through its extensive use in TCM. Recent studies also found that aqueous extracts of Radix Salviae can inhibit the devel‐ opment of liver cancer by suppressing the metastasis and recurrence in animal models [21]. *In vitro* study showed that Radix Salviae treatment significantly decreased the expression of Intercellular Adhesion Molecule 1(ICAM‐1) in SMMC‐7721 cells. In addition, it could suppress the invasion of SMMC‐7721 cell and make the fibronectin‐attached cells exfoliated. The cell adhesion ability of HCC‐HCC, HCC‐lymphocyte and HCC‐endothelial cell also decreased after Radix Salviae treatment. The tumor xenograft mice model also confirmed the antimeta‐ stasis effects of Radix Salviae on posthepatectomy liver cancer *in vivo*.

**4.2. Chinese medicines and their active compounds for inducing liver cancer cells**

Panaxydol is one of the bioactive components in Panax Notoginseng (Sanqi in TCM). Panax Notoginseng is a famous hemostatic in TCM and it can also relieve other blood disorders, such as blood stasis or blood deficiency. Recent studies have shown that the panaxydol could induce cell differentiation in human HCC cell lines SMMC‐7721 [36]. Ultrastructure morphology observation confirmed that there have obvious cell morphologic changes after panaxydol treatment. The activity of several differentiation related proteins such as alkaline phosphatase and albumin were increased, while AFP activity was significantly decreased after panaxydol treatment. These results showed that panaxydol may be a potential antihepatoma agent by

Gepsin can also inhibit liver cancer development by inducing cancer cells differentiation. Studies showed that after gepsin treatment, the HCC cell line Bel‐7402 presents ultrastructural morphology of differentiation. Western blot results revealed that the differentiation related proteins such as the AFP protein secretion significantly decreased, while ALB protein expres‐

Ginseng is one of the most widely used herbs in TCM for thousands of years. Ginsenosides are the main bio‐active components in Ginseng. There are many reports verified the anticancer effect of ginsenosides *in vitro* and *in vivo*. For example, ginsenosides‐Rh2 (G‐Rh2) can inhibit the proliferation of SMMC‐7721 cells as well as induce the mature and normality of cell ultrastructure morphology. The expression of AFP, gamma‐GT and heat‐resistant ALP were

**4.3. Chinese medicines and their active compounds for averting the invasion and metastasis**

Ardipusilloside I is a triterpene‐saponin separated from the TCM herbs *Ardisia pusilla* A. DC. Recent studies have revealed its anticancer effects through inhibition invasion and metastasis of HCC cells [38]. Both *in vitro* and *in vivo* studies demonstrated that Ardipusilloside I may suppress migration of HCC cells partially by decreasing the expression of the metalloprotei‐ nase (MMP)‐2 and MMP‐9 proteins. In addition, Ardipusilloside I can activate Rac1 protein and further induce E‐cadherin which may result in inhibition of cancer cells migration.

As we have discussed earlier, GSPP and its monomeric protein gepsin are effective in inhibiting the proliferation of HCC cells. Recent studies found that GSPP was also effective in suppressing the migration of HCC cells [33]. GSPP treatment remarkably decreased the concentration of intracellular calcium. Many studies have demonstrated that low intracellular calcium concen‐ tration is associated with reduced cancer migration. GSPP treatment could remarkably decrease the concentration of intracellular calcium. Thus, the antimigration effect by GSPP may be partially a consequence of downregulation of intracellular calcium concentration

The hepatic protective effects of Radix Salviae have been verified through its extensive use in TCM. Recent studies also found that aqueous extracts of Radix Salviae can inhibit the devel‐

together with an upregulation of actin filaments polymerization in HCC cells.

sion was obviously up‐regulated on gepsin‐treated cancer cells [34].

also significantly decreased after 10 mg/ml G‐Rh2 treatment [37].

**differentiation**

inducing tumor cell differentiation.

54 Anti-cancer Drugs - Nature, Synthesis and Cell

**of liver cancer cells**

Curcumin, a polyphenol isolated from the rhizome of Curcuma longa (Jiang in TCM) has potential anti‐cancer effects in many types of cancers. However, due to its poor aqueous solubility, the clinical application of curcumin has been limited. A recent study has used the polymeric nanoparticle formulation of curcumin to improve its solubility as well as anticancer activity [39]. The results showed that when used as a combination with sorafenib, the modified curcumin can suppress the proliferation and invasion of HCC cells *in vitro*. Furthermore, *in vivo* study also found curcumin could inhibit liver cancer growth and lung metastases. Mechanisms study found curcumin and sorafenib synergistically inhibited the expression of MMP9 by down‐regulating NF‐kappaB/p65‐signaling pathway. Taken together, the polymeric nanoparticle formulation of curcumin may exhibit antitumor activity by inhibiting liver cancer metastasis.
