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

3.10. Black Cohosh

Black cohosh, also known as Cimicifuga racemosa or Actaea racemosa (family of Ranunculaceae), is a popular phytotherapeutic product frequently used for women’s health concerns such as premenstrual syndrome, dysmenorrhoea, and menopausal symptoms [3, 340]. A recent meta-analysis of nine controlled placebo clinical trial confirmed the efficacy of its use in relieving menopausal symptoms [341].

This plant is included in the famous patent medicine Lydia Pinkham’s Vegetable Compound and was listed in the 19th century Pharmacopoeia [342]. Black cohosh contains unidentified substances with selective oestrogen receptor modulator properties; however, triterpenes glycosides have been assumed to be the crucial constituents for its biological effects [342].

Few in vitro tests using breast cancer cell lines in culture and in vivo animal studies evaluating the effect of black cohosh as chemopreventive or anticancer agents are reported in literature. Several components extracted from black cohosh were tested in human breast cancer cells revealing anticancer properties: cycloartane triterpenoids induced mitochondrial apoptosis and cell cycle arrest, via Raf/MEK/ERK signalling pathway and Akt phosphorylation [343] or via NF-κB signalling pathway [344]. Actein revealed an antiangiogenic effect by inhibiting the proliferation and reduced the migration and motility of endothelial cells (in vitro). Oral administration of actein at 10 mg/kg for 7 days inhibited blood vessel formation and oral actein treatments (10–15 mg/kg) for 28 days resulted in decreasing mouse 4T1 breast tumour sizes and metastasis to lungs and liver [345]. Nevertheless, some contradictory conclusions have been indicated. For example, Einbond et al. conjugated a triterpene glycoside of black cohosh and actein to liposomes [346]. This vehicle increased the growth inhibition activity of actein against human breast cancer cells. Actein presented antiproliferative action by modulation of the NF-ƙB and MEK pathways. Using female Sprague-Dawley rats, Weissenstein and colleagues indicated that black cohosh could be chemopreventive or chemotherapeutic agents for mammary cancer due to its immunohistochemistry effect [347]. However, Davis and collaborators suggested that black cohosh may increase metastatic mammary cancer in MMTV-neu mouse model which is used due to its similarities to HER2(+) breast cancer [348].

Black cohosh is one of the most controversial natural therapies used among breast cancer patients due to its ambiguous estrogenic or antiestrogenic activities with many studies in literature exploring considerable debate over the safety of its uses [349]. Under conditions of excessive estrogen, the active ingredients of this plant may behave as estrogen antagonists by a mechanism of competitive inhibition of the ER. However, in the presence of low estrogen, actives may act as weak agonists [350–352]. If black cohosh exhibits estrogenic activity, it may result in potentially negative outcomes on breast cancer risk or recurrence, mainly in women undergoing antiestrogen therapy [353]. However, Fritz and collaborators carried out a systematic review about the use of black cohosh in breast cancer and found that evidence is conflicting in all analysed aspects [81]. The authors concluded that current evidence does not sustain an association between black cohosh and increased risk of breast cancer (results from observational studies) and reduce evidence that supports the efficacy of black cohosh for reduction of hot flashes in breast cancer patients (results from observational studies and clinical trials). Some limitations of studies include subjective outcomes, different risk of bias, namely, lack of blinding and inadequate reporting of withdrawals (for clinical trials); variation of dose and duration schedules of black cohosh, different products and methods of extraction, and lack of information and criteria included in the retrospective design (for observational studies). In addition, black cohosh seems to have limited and no classic estrogenic activity as seen by its effect on bone metabolism.

Different conclusions have also been reported concerning the potential for interactions with antiproliferative effects of different classes of chemotherapy agents. A cohort study suggested that taking black cohosh can reduce risk of recurrence in patients taking tamoxifen [82]. No risk of recurrent and no consistent serious adverse events related to the combination of black cohosh and tamoxifen were reported in clinical trials [354, 355]. No interaction on the formestane- (i.e., an aromatase inhibitor-) induced tumour reduction was observed with the coadministration of black cohosh extract in a chemically induced rat model for mammary carcinoma [356]. In humans, different findings were reported [357, 358].

The Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynaecologists list black cohosh interactions with some drugs including anesthetics, antihypertensives, and sedatives [359]. Despite this, Walji et al. conducted a systematic review and suggested that black cohosh has a high safety profile in cancer patients; however, the authors did not include recent evidence [360]. In another study based on animal studies, Freudenstein and colleagues suggested that Cimicifuga racemosa extract is safe for treatment of menopausal symptoms in breast cancer survivors in whom hormone-replacement therapy is contraindicated [361]. Case reports of hepatotoxicity have been reported but confounding factors such as “poor case data quality, uncertain of black cohosh product, quality, and insufficient adverse event definition” could justify this adverse effect [362].

The outcome of black cohosh uses in women with or without a history of breast cancer is unclear and its use must be discouraged.