Scutellaria baicalensis and Cancer Treatment: Recent Progress and Perspectives in Biomedical and Clinical Studies

Traditional Chinese medicines have been recently recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects of cancer chemotherapies however their healing mechanisms are still largely unknown. Scutellaria baicalensis is one of the most popular and multi-purpose herb used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections. Accumulating evidence demonstrate that Scutellaria also possesses potent anticancer activities. The bioactive components of Scutellaria have been confirmed to be flavones. The major constituents of Scutellaria baicalensis are Wogonin, Baicalein and Baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The antitumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-kappaB activity, to inhibit several genes important for regulation of the cell cycle, to suppress COX-2 gene expression and to prevent viral infections. The tumor-selectivity of Wogonin has recently been demonstrated to be due to its ability to differentially modulate the oxidation-reduction status of malignant vs. normal lymphocytic cells and to preferentially induce phospholipase C gamma 1, a key enzyme involved in Ca(2+) signaling, through H(2)O(2) signaling in malignant lymphocytes. This review is aimed to summarize the research results obtained since the last 20 years and to highlight the recently discovered molecular mechanisms.

Coptidis rhizoma (huanglian) and its major component, berberine, have drawn extensive attention toward their antineoplastic effects in the recent years. The antineoplastic effects are related to the Chinese Medicine (CM) properties of huanglian in treating diseases by removing damp-heat and purging fire and counteracting toxicity. To trace the long history of the traditional use of huanglian from folk medicines, especially from Chinese medicine, to recent pharmacological studies of huanglian and berberine, with an emphasis on their antineoplastic effects and the promise as novel antineoplastic agents. A total of seven databases were extensively searched for literature research. The terms and keywords for searching included huanglian, berberine, Coptis, Coptidis rhizoma, anticancer, anti-invasion, antimatastasis and mechanism. The papers including ours with studies on anticancer and mechanism, pharmacology and toxicology of huanglian and/or berberine were focused. In view of traditional use, the anticancer effects of huanglian can be ascribed to its CM trait by removing damp-heat, fire and toxicity. From modern biomedical studies, anticancer effects have been demonstrated in both huanglian and berberine. The underlying molecular mechanisms involve cell-cycle arrest, apoptosis induction and anti-inflammation. Berberine is an essential anticancer compound in huanglian. In some studies, the use of huanglian was shown to be more effective and beneficial than the use of berberine alone. The presence of other protoberberine-type alkaloids in huanglian might give synergistic effects for the anticancer effects. Berberine also demonstrates effects of antiangiogenesis, anti-invasion and anti-metastasis in some cancer cell lines, however, more investigations are required to unravel the underlying mechanisms involved. The modern evidences of treating cancer with huanglian and berberine have a strong linkage with traditional concept and rules of using huanglian in CM practice. As anticancer candidates with low toxicity, berberine and its altered structure, as well as huanglian and its formulae, will attract scientists to pursue the potential anticancer effects and the mechanisms by using technologies of genomics, proteomics and other advanced approaches. On the other hand, relatively few in vivo studies have been conducted on anticancer effects of huanglian and berberine. The clinical application of berberine or huanglian as novel cancer therapeutic agents requires in vivo validations and further investigations of their anticancer mechanisms.

The plasticity of tumour-associated macrophages (TAMs) has implicated an influential role in hepatocellular carcinoma (HCC). Repolarisation of TAM towards M1 phenotype characterises an immune-competent microenvironment that favours tumour regression. To investigate the role and mechanism of TAM repolarisation in suppression of HCC by a natural compound baicalin, Orthotopic HCC implantation model was used to investigate the effect of baicalin on HCC; liposome-clodronate was introduced to suppress macrophage populations in mice; bone marrow-derived monocytes (BMDMs) were induced to unpolarised, M1-like, M2-like macrophages and TAM using different conditioned medium. We observed that oral administration of baicalin (50 mg/kg) completely blocked orthotopic growth of implanted HCC. Suppression of HCC by baicalin was diminished when mice macrophage was removed by clodronate treatment. Baicalin induced repolarisation of TAM to M1-like phenotype without specific toxicity to either phenotype of macrophages. Baicalin initiated TAM reprogramming to M1-like macrophage, and promoted pro-inflammatory cytokines production. Co-culturing of HCC cells with baicalin-treated TAMs resulted in reduced proliferation and motility in HCC. Baicalin had minimal effect on derivation of macrophage polarisation factors by HCC cells, while directly induced repolarisation of TAM and M2-like macrophage. This effect was associated with elevated autophagy, and transcriptional activation of RelB/p52 pathway. Suppression of autophagy or RelB abolished skewing of baicalin-treated TAM. Autophagic degradation of TRAF2 in baicalin-treated TAM might be responsible for RelB/p52 activation. Our findings unveil the essential role of TAM repolarisation in suppressive effect of baicalin on HCC, which requires autophagy-associated activation of RelB/p52.