The IL-6/STAT3 Signaling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells

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.

The Influence of In Vitro Gastrointestinal Digestion on the Anticancer Activity of Manuka Honey

“…cancer cell line (LoVo) where a concentration of 50 mg/mL reduced colony formation by up to 80% [37], and in one breast cancer line (MDA-MB-231), where the higher concentration of MH decreased this value by up to 60% [59]. Similar results were obtained with propolis, which decreased the colonigenic capacity of two cell lines of glioblastoma (U251, U343) [60].…”

“…In the other two concentrations tested (16 and 24 mg/mL), the decrease in the number of formed colonies for both treatments was almost similar, up to a decrease of about 65% compared to the control. This activity of MH has also been confirmed in another colon cancer cell line (LoVo) where a concentration of 50 mg/mL reduced colony formation by up to 80% [37], and in one breast cancer line (MDA-MB-231), where the higher concentration of MH decreased this value by up to 60% [59]. Similar results were obtained with propolis, which decreased the colonigenic capacity of two cell lines of glioblastoma (U251, U343) [60].…”

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

“…The effect of Ambrisentan on cancer cell viability was carried out using MDA-MB-231 cells, as detailed previously 25 . Briefly, MDA-MB-231 cells (5 × 10 3 cells/well) were seeded overnight in 96-well plate and then cultured in triplicate for 24 h with Ambrisentan dissolved in 0.1% DMSO.…”

“…2b). However, the migration and invasion capacities of MDA-MB-231 cells, which are known to contribute to the tumorigenicity of these triple-negative breast cancer cells 25 were significantly inhibited after a 24 h-exposure to Ambrisentan in a dose-dependent manner ( Fig. 2c, d).…”

Metformin - A Panacea Pharmaceutical Agent through convergence revolution initiative

“…Several plausible molecular mechanistic pathway has been reported for metformin's antineoplastic action on the basis several in vitro studies. Several proposed mechanisms are: • Decreased LKB1 thereby a reduction AMPK levels resulting in mTOR activation followed by decreased S6 kinase activation 32 • Increased expression of REDD1 resulting in diminished mTOR activation followed by decreased S6 kinase activation 33 • Inhibition of STAT3 facilitating and enhancing apoptosis induction 34 • Alteration of the expression oncological associated miRNAs namely, miRNA let7A and miRNA-181 35 Metformin affects cell signaling pathways directly or indirectly at multiple points. For this reason, the drug may be useful against numerous cancer types.…”