Abstract
There is renewed interest in the potential use of natural compounds in cancer therapy. Previously, we demonstrated the anti-tumor properties of manuka honey (MH) against several cancers. However, the underlying mechanism and molecular targets of this activity remain unknown. For this study, the early targets of MH and its modulatory effects on proliferation, invasiveness, and angiogenic potential were investigated using two human breast cancer cell lines, the triple-negative MDA-MB-231 cells and estrogen receptor-positive MCF-7 cells, and the non-neoplastic breast epithelial MCF-10A cell line. Exposure to MH at concentrations of 0.3–1.25% (w/v) induced a dose-dependent inhibition of the proliferation of MDA-MB-231 and MCF-7, but not MCF-10A, cells. This inhibition was independent of the sugar content of MH as a solution containing equivalent concentrations of its three major sugars failed to inhibit cell proliferation. At higher concentrations (>2.5%), MH was found to be generally deleterious to the growth of all three cell lines. MH induced apoptosis of MDA-MB-231 cells through activation of caspases 8, 9, 6, and 3/7 and this correlated with a loss of Bcl-2 and increased Bax protein expression in MH-treated cells. Incubation with MH induced a time-dependent translocation of cytochrome c from mitochondria to the cytosol and Bax translocation from the cytosol into the mitochondria. MH also induced apoptosis of MCF-7 cells via the activation of caspases 9 and 6. Low concentrations of MH (0.03–1.25% w/v) induced a rapid reduction in tyrosine-phosphorylated STAT3 (pY-STAT3) in MDA-MB-231 and MCF-7 cells. Maximum inhibition of pY-STAT3 was observed at 1 h with a loss of >80% and coincided with decreased interleukin-6 (IL-6) production. Moreover, MH inhibited the migration and invasion of MDA-MB-231 cells as well as the angiogenic capacity of human umbilical vein endothelial cells. Our findings identify multiple functional pathways affected by MH in human breast cancer and highlight the IL-6/STAT3 signaling pathway as one of the earliest potential targets in this process.
Highlights
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]
Incubation of MDA-MB-231 (Figures 1A,B) or MCF-7 (Figures 1C,D) breast cancer cells with manuka honey (MH) resulted in significant loss of viability, which was dependent on time of exposure and concentration of MH used in culture
Our results suggest that MCF-7 cells were relatively more resistant to MH-induced growth inhibition compared to MDA-MB-231 cells
Summary
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 favorable treatment outcome is still a challenge, 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 [4,5,6]
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