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Mol Carcinog. 2018 Mar;57(3):333-346. doi: 10.1002/mc.22758. Epub 2017 Nov 24.

Eugenol potentiates cisplatin anti-cancer activity through inhibition of ALDH-positive breast cancer stem cells and the NF-κB signaling pathway.

Author information

1
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
2
Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
3
Faculty of Life Science, University of Manchester, Manchester, United Kingdom.
4
Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
5
Faculté des Sciences Fès, Laboratoire de Biotechnologie Atlas, Fès, Morocco.

Abstract

Triple-negative breast tumors are very aggressive and contain relatively high proportion of cancer stem cells, and are resistant to chemotherapeutic drugs including cisplatin. To overcome these limitations, we combined eugenol, a natural polyphenolic molecule, with cisplatin to normalize cisplatin mediated toxicity and potential drug resistance. Interestingly, the combination treatment provided significantly greater cytotoxic and pro-apoptotic effects as compared to treatment with eugenol or cisplatin alone on several triple-negative breast cancer cells both in vitro and in vivo. Furthermore, adding eugenol to cisplatin potentiated the inhibition of breast cancer stem cells by inhibiting ALDH enzyme activity and ALDH-positive tumor initiating cells. We provide also clear evidence that eugenol potentiates cisplatin inhibition of the NF-κB signaling pathway. Indeed, the binding of NF-κB to its cognate binding sites present in the promoters of IL-6 and IL-8 was dramatically reduced, which led to potent down-regulation of the IL-6 and IL-8 cytokines upon combination treatment relative to the single agents. Similar effects were observed on proliferation, inhibition of epithelial-to-mesenchymal transition and stemness markers in tumor xenografts. These results provide strong preclinical justification for combining cisplatin with eugenol as therapeutic approach for triple-negative breast cancers through targeting the resistant ALDH-positive cells and inhibiting the NF-κB pathway.

KEYWORDS:

ALDH; NF-κB; breast cancer stem cells; cisplatin; eugenol

PMID:
29073729
DOI:
10.1002/mc.22758
[Indexed for MEDLINE]

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