Phytotherapy and Nutritional Supplements on Breast Cancer 用于乳腺癌治疗的植物疗法和营养补充剂

3.3. Salvia

Salvia is the largest and the most important genus of the family Labiatae [89]. This genus includes wild growing and cultivated medicinally valuable species (e.g., Salvia bracteata and Salvia rubifolia) as well as ornamentals.Salvia species present a high diversity in their secondary metabolites (e.g., flavonoids, diterpenoids, volatile oils, and tannins) which justify the multiple pharmacological effects reported in the literature [90].

In breast cancer, different species were investigated for their in vitro antiproliferative activity. Abu-Dahab et al. [90] demonstrated that the ethanol extract of three species, namely, S. syriaca, S. fruticosa, and S. horminum, presented selective antiproliferative activity against oestrogen receptor (ER) positive breast cancer cell lines with minimum toxicity against normal human periodontal fibroblasts. Based on their safe and selective effects, the authors suggested the use of these Salvia species as promising plant-originated anticancer agents. Other species also showed promising results. S. triloba and S. dominica ethanol extracts showed antiproliferative effects on adenocarcinoma of breast cell line (MCF7, oestrogen receptor-positive) and human ductal breast epithelial tumour cell line (T47D) via proapoptotic cytotoxic mechanisms [91]. S. miltiorrhiza (i.e., Danshen which is widely used in traditional Chinese medicine) exhibited a strong inhibitory effect on the proliferation of MCF-7 breast cell line and induced cell cycle delay in the G1 phase via modulation of Akt phosphorylation and p27 level [92]. Authors also used MCF-7 HER2 cell line which over expresses HER2. HER2 (i.e., human epidermal growth factor receptor type 2) is a receptor tyrosine kinase and is involved in signal transduction pathways leading to tumour cell proliferation. HER2 is overexpressed in a high percentage of breast cancer (25–30%) and its overexpression is associated with aggressive tumours, a high rate of metastasis and relapse, poor prognosis, and limitation in treatment (in most cases it became resistant to endocrine therapy such as tamoxifen) [93, 94]. The MCF-7 HER2 cells were more resistant to the Danshen actions.

Danshen extracts contain diterpene quinone and phenolic acid derivatives such as tanshinone (I, IIA, and IIB), cryptotanshinone, isocryptotanshinone, miltirone, tanshinol (I and II), and salviol [95]. These compounds are antioxidant agents and protect against lipid peroxidation. Some of these compounds have been isolated from Danshen, sometimes synthesized, and their in vitro cytotoxic activity tested against diverse cancer cell lines, including breast cancer [96–99]. Besides the in vitro inhibition of ER-positive human cancer cells lines, Wang and collaborators also proved that neotanshinlactone was more potent and more selective than tamoxifen citrate [96]. In this area, only one in vivo study has reported anticancer activity on mice bearing human breast infiltrating duct carcinoma orthotopically [95], where the compound tanshinone II A strongly inhibited the in vitro proliferation of ER-positive breast cancer cells and inhibited in vivo growth of ER-negative breast cancer. The inhibition of proliferation and apoptosis induction of cancer cells through upregulation and downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis, signal transduction, transcriptional regulation, angiogenesis, invasive potential, and metastatic potential of cancer cells could explain in part the anticancer effect of this compound. Chemotherapy resistance is a significant problem in breast cancer therapy. Cai et al. reported the reversal mechanism of salvianolic acid A (i.e., a phenolic active compound extract from Salvia miltiorrhiza) in human breast cancer paclitaxel resistance cell line, facilitating the sensitivity of chemotherapeutic agents [100]. In another study, the authors demonstrated that tanshinone II A ameliorated hypoxia-induced chemotherapy resistance to doxorubicin and epithelial-mesenchymal transition in breast cancer cell lines via downregulation of hypoxia-induced factor 1α expression [101]. However, in vivo studies are required to support these achievements.

Wong et al. performed a clinical trial and concluded that the coadministration of Coriolus versicolor (Yunzhi, 50 mg/kg body weight, 100% polysaccharopeptide) and Salvia miltiorrhiza (Danshen, 20 mg/Kg body weight) could be a promising approach to improve immunological function in posttreatment breast cancer patients [54]. Patients supplemented for 6 months presented significantly elevated values of absolute counts of T-helper lymphocytes, the ratio of T-helper/T suppressor and cytotoxic lymphocytes, and the percentage and absolute counts of B-lymphocytes and decreased values of plasma sIL-2R concentration. In other clinical study, the intravenous administration of Salvia miltiorrhiza extract was able to reduce ischemia and necrosis of skin flaps after mastectomy as well as anisodamine administration but with no adverse effects [55].