Date of Award

12-2015

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Medical Education

First Advisor

Prof. Basel K. al-Ranuu/i

Second Advisor

Dr. Maria J. Femamlez-Cabezudo

Third Advisor

Prof. Samir Attoub

Abstract

The medicinal properties of Manuka honey have been extensively studied, particularly in terms of its wound healing and antimicrobial activities. We have previously demonstrated that Manuka honey also has anti-cancer properties against a variety of cancer cell types in vitro as well as in preclinical cancer models. The cellular targets of the anti-cancer activity of Manuka honey, however, remain unknown. For the present study, we selected the triple negative human breast cancer cell line, MDA-MB-231, to investigate susceptibility to Manuka honey and to identify the potential signaling pathways affected. MDA-MB-231 cancer cells are known to constitutively express activated STAT3 transcription factor. This is due to mutations in upstream tyrosine kinases that effectively maintain STAT3 in a phosphorylated, and thus activated, form. These cells are also known to secret IL-6 constitutively, thus creating a positive feedback loop that drives their proliferation and survival. Our findings demonstrate that treatment with Manuka honey led to inhibition of STAT3 tyrosine phosphorylation in a concentration and time-dependent manner. Inhibition of STAT3 activity was observed as early as 15 minutes after cell co-culture with as little as 1% solution of Manuka honey. Importantly, treatment with Manuka honey also led to decreased IL-6 production. As a consequence, we observed a reduction in the level of antiapoptotic protein Bcl-2 and an increased in the protein expression of cytochrome c, ultimately leading to the death of cancer cells. Heat-treatment of Manuka honey abolished its effect on STAT3 phosphorylation and cytocidal capacity. In conclusion, our findings identify novel targets affected by treatment with Manuka honey in triple negative human breast cancer cells. The influence of the blockade of this pathway by Manuka honey on other types of human cancers remains to be investigated.

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