Excerpt from original Manuka Honey Science research article published by frontiersin.org
The IL-6/STAT3 Signalling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells
Breast cancer is the most prevalent cancer among women worldwide with a mortality rate of >500,000 annually, 62% of deaths occurring in developing countries (1). Despite improved screening and early detection, a favourable treatment outcome is still a challenge, particularly for triple-negative breast cancers (TNBCs). TNBCs are so named because they lack expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor-2. Patients with TNBCs have poor prognosis due to inherent resistance of their cancers to chemotherapy treatment, leading to increased risk of recurrence (2). Another major challenge in breast cancer treatment is the development of metastasis, since metastatic breast cancer cells are frequently resistant to almost all available therapies (3). Given the limitations in currently used treatment modalities, including chemotherapy, radiotherapy, and surgery, and their associated toxicities, for breast and other types of cancers, complementary/alternative medicine approaches have received increasing attention over the past few years (4–6).
Previously, we demonstrated that low concentrations of manuka honey (MH) can effectively inhibit the growth of several types of cancer cells, including melanoma, breast adenocarcinoma, and colorectal cancer (7). Moreover, using a preclinical model of implantable melanoma, systemic administration of MH enhanced the anti-tumor activity of paclitaxel and improved overall host survival (7). Several groups have also reported on the anti-tumor activity of various types of honey on cancer cells [see Ref. (8) for a recent review]. However, with few exceptions (9–11), most of these studies were carried out using in vitro systems. The anti-proliferative and pro-apoptotic properties of honey on cancer cells are thought to be mainly due to its phenolic compound constituents, including chrysin, luteolin, quercetin, and caffeic acid esters (12–15). We and others demonstrated that honey induces caspase-mediated apoptosis in different cancer cell lines, such as melanoma, breast, cervical, prostate, renal, and liver cancers (16–21). However, what remains largely unknown is the nature of the earliest upstream target in cancer cells that is affected by honey treatment.
For this study, we selected two human breast cancer cell lines, the triple-negative MDA-MB-231 and the ER-positive MCF-7 cells, to investigate susceptibility to MH and to identify the earliest signalling pathways affected. We demonstrate that MH prevents the growth of cancer cells in a time and dose-dependent manner. Moreover, treatment with low concentrations of MH (≤1%) led to an inhibition of cancer cell migration and invasion capacity. With regard to the potential signalling pathway involved, our study demonstrate that treatment of MDA-MB-231 and MCF-7 cancer cells with MH led to a dose- and time-dependent inhibition of pY-STAT3, which was observed as early as 15 min after cell exposure to <1% solution of MH. Importantly, treatment with MH also led to decreased interleukin-6 (IL-6) production by both cancer cell lines. These findings identify the IL-6/STAT3 signalling pathway as an early molecular target of MH in human cancer and reveal the important consequences of this inhibition on multiple effector functions of breast cancer cells.