Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis.

Traditional Chinese medicine (TCM) has been a major part of healthcare in China, and has extensively affected medicine and healthcare in surrounding countries over a long period of time. In the fight against cancer, certain anticancer remedies using herbs or herbal formulas derived from TCM have been developed for the management of malignancies. Furthermore, there are clinical trials registered for the use of herbal remedies in cancer management. Herbal medicine has been used as part of combined therapies to reduce the side-effects of chemotherapy, including bone marrow suppression, nausea and vomiting. Herbal remedies have also been used as chemopreventive therapies to treat precancerous conditions in order to reduce the incidence of cancer in high-risk populations. Emerging evidence has revealed that herbal remedies can regulate the proliferation, apoptosis, adhesion and migration of cancer cells. In addition to this direct effect upon cancer cells, a number of herbal remedies have been identified to suppress angiogenesis and therefore reduce tumour growth. The inhibition of tumour growth may also be due to modifications of the host immune system by the herbal treatment. However, the precise mechanisms underlying the therapeutic effects of herbal remedies remain poorly understood and are yet to be fully elucidated. The present study aims to summarize the current literature and clinical trial results of herbal remedies for cancer treatment, with a particular focus on the recent findings and development of the Yangzheng Xiaoji capsule.

YangZheng XiaoJi exerts anti-tumour growth effects by antagonising the effects of HGF and its receptor, cMET, in human lung cancer cells.

BACKGROUND: Hepatocyte growth factor (HGF) is a cytokine that has a profound effect on cancer cells by stimulating migration and invasion and acting as an angiogenic factor. In lung cancer, the factor also plays a pivotal role and is linked to a poor outcome in patients. In particular, HGF is known to work in combination with EGF on lung cancer cells. In the present study, we investigated the effect of a traditional Chinese medicine reported in cancer therapies, namely YangZheng XiaoJi (YZXJ) on lung cancer and on HGF mediated migration and invasion of lung cancer cells. METHODS: Human lung cancer cells, SKMES1 and A549 were used in the study. An extract from the medicine was used. Cell migration was investigated using the EVOS and by ECIS. Cell-matrix adhesion and in vitro invasion were assessed. In vivo growth of lung cancer was tested using an in vivo xenograft tumour model and activation of the HGF receptor in lung tumours by an immunofluorescence method. RESULTS: Both lung cancer cells increased their migration in response to HGF and responded to YZXJ by reducing their speed of migration. YZXJ markedly reduced the migration and in vitro invasiveness induced by HGF. It worked synergistically with PHA665752 and SU11274, HGF receptor inhibitors on the lung cancer cells both on HGF receptor activation and on cell functions. A combination of HGF and EGF resulted in a greater increase in cell migration, which was similarly inhibited by YZXJ, and in combination with the HGF receptor and EGF receptor inhibitors. In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth. It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours. CONCLUSION: YZXJ has a significant role in reducing the migration, invasion and in vivo tumour growth of lung cancer and acts to inhibit the migratory and invasive effects induced by HGF and indeed by HGF/EGF. This effect is likely attributed to the inhibition of the HGF receptor activation. These results indicate that YZXJ has a therapeutic role in lung cancer and that combined strategy with methods to block HGF and EGF should be considered.

Expression of Sonic Hedgehog (SHH) in human lung cancer and the impact of YangZheng XiaoJi on SHH-mediated biological function of lung cancer cells and tumor growth.

Sonic Hedgehog (SHH) is a protein that is aberrantly expressed in various human tumors. SHH and its signaling molecules have been indicated as potential therapeutic targets. In the present study, we evaluated the expression of SHH transcript in human non-small cell lung cancer (NSCLC) tissues and investigated the impact of inhibiting SHH together with a traditional Chinese medicine formula, YangZheng XiaoJi (YZXJ), on the function and growth of lung cancer cells. Human NSCLC tissues had significantly higher levels of the SHH transcript compared matched normal lung tissues (n=83). TNM2 tumors and tumors with pleural invasion had higher levels than TNM1 and non-invasive tumors. High SHH levels were associated with a shorter overall survival (OS) of the patients. A SHH inhibitor, cyclopamine, and YZXJ alone or in combination had a marked inhibitory effect on cellular invasion and cellular migration of human lung cancer cells, A549 and SKMES1. YangZheng XiaoJi and its combination with cyclopamine also significantly reduced the growth of lung tumors in vivo together with a reduction of SHH and smoothened (Smo) proteins in the lung tumors. The present study provides evidence that blocking SHH by way of small inhibitor and by YangZheng XiaoJi has a profound influence on lung cancer cells as seen by in vitro invasion and cell migration and in vivo tumor growth. Together with the aberrant expression of SHH in NSCLC tumors in the patients, it is suggested that SHH is a potential target for therapies for NSCLC.

Molecular angiogenic events of a two-herb wound healing formula involving MAPK and Akt signaling pathways in human vascular endothelial cells.

The emergence of electric cell-substrate impedance sensing (ECIS) technology has provided new insight in advanced cell behavioral study by its nanometer sensitivity, precise electrical wounds generation, and high reproducibility that can be monitored in real time in a noninvasive way. However, little is known regarding pro-angiogenic agents in wound healing studies using endothelial cells evaluated with ECIS technology. Our previous studies showed a prominent wound healing effect of a two-herb formula (NF3) comprising of Astragali Radix and Rehmanniae Radix in a rat chronic wound model through actions including angiogenesis. Here we further investigated the angiogenic effect and its underlying molecular mechanism through proliferation, motility, and tubule formation of human vascular endothelial cells (HECV) using ECIS technology. It was first shown that HECV treated with NF3 had a higher resistance than that of control using ECIS cell attachment and cell migration model (p < 0.01). We further validated in a scratch assay that NF3 treatment significantly stimulated HECV cell migration (p < 0.01-0.05). Also, NF3-treated HECV were observed to develop into a significantly more branched tubular structure when compared with control (p < 0.05-0.01). Meanwhile, Western blot analysis of NF3-treated HECV revealed the activated expression of p-Akt, and mitogen-activated protein (MAP) kinases for p-ERK, p-p38, and p-JNK. We propose that the effect of NF3 in the promotion of endothelial cell migration and tubule formation could be mediated through pathways involving p-Akt and activated MAP kinases. Hence, we demonstrated the complexity of the angiogenic effect activated by NF3 molecularly and functionally. NF3 treatment could offer therapeutic value to chronic wound healing for its pro-angiogenic efficacy.