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Free Radic Biol Med. 2018 Oct;126:41-54. doi: 10.1016/j.freeradbiomed.2018.07.014. Epub 2018 Jul 26.

Manuka honey synergistically enhances the chemopreventive effect of 5-fluorouracil on human colon cancer cells by inducing oxidative stress and apoptosis, altering metabolic phenotypes and suppressing metastasis ability.

Author information

1
Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)-Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, 60131 Ancona, Italy.
2
Department of Physiology, Institute of Nutrition and Food Technology "Jose Mataix", Biomedical Research Centre, University of Granada, Spain.
3
Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)-Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, 60131 Ancona, Italy. Electronic address: m.a.battino@univpm.it.

Abstract

The development of chemo-sensitizers is urgently needed to overcome 5-fluorouracil (5-FU) therapeutic resistance and adverse toxicity in colorectal cancer. This work aims to evaluate the synergic effects of 5-FU and Manuka honey (MH), a rich source of bioactive compounds, in enhancing the anticancer effects of this drug on human colon cancer HCT-116 and LoVo cells. Compared to 5-FU alone, MH synergistically enhanced the chemotherapeutic effects of 5-FU, by reducing cell proliferation through the suppression of EGFR, HER2, p-Akt and p-mTOR expression, and promoting apoptosis by the modulation pro-apoptotic (p53, Bax, Cyto c, FasL caspase-3, -8, -9 and cleave-PARP) and anti-apoptotic (Bcl-2) markers. The activations of p-p38MAPK and p-Erk1/2 pathways and ROS production were also involved in this process. Downregulation of transcription factor (NF-κB and Nrf2) and antioxidant enzyme activity (SOD, catalase, glutathione peroxidase and glutathione reductase) and expression (SOD, catalase and HO-1) were more evident after the combined treatment, leading to more cell death by oxidative stress. Moreover, additive effects were also observed by increasing lipid and protein oxidation and arresting cell cycle. All the parameters of mitochondrial respiration and glycolysis function decreased and both cells entered the quiescent stage after the combined treatments. MH also influenced the anti-metastasis effects of 5-FU by decreasing migration ability, suppressing the expression of MMP-2, MMP-9 and increasing N-cadherin and E-cadherin. In conclusion, MH could be a useful preventive or adjuvant agent in the treatment of colorectal cancer with 5-FU.

KEYWORDS:

5-Fluorouracil; Apoptosis; Colon cancer; Manuka honey; Reactive oxygen species; Synergistic effect

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