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Significance Statement
To determine synergistic or additive effects of the drug combinations, a Combination Index (CI) was used following the procedure developed by Fischel (Fischel et al., 2005), with the equation adapted from the method developed previously by Chou and Talalay (Chou and Talalay 1984). According to Fischel, R= Apoptosis (Nisin + Cisplatin)/ (Nisin alone x Cisplatin alone)
if:
R< 0.8, then the association is considered to be synergistic;
0.8 < R < 1.2, then the association is considered to be additive;
R > 1.2, then the association is considered to be antagonistic.
Thus, R=61.7/28.6 x 12.3=61.7/351.8=0.175; R<0.8 thus the drug interaction is synergistic.
Fischel, J. L.; Formento, P.; Milano, G., Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors. British journal of cancer 2005, 92 (6), 1063-1068.
Chou, T. C.; Talalay, P., Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Advances in enzyme regulation 1984, 22, 27-55.
Figure Legend: Oral Cancer Cells Treated with Nisin and Undergoing Apoptotic Cellular Changes.
Figure. Nisin Synergizes with Cisplatin to induce Apoptosis in HNSCC cells that are highly resistant to ionizing radiation and Cisplatin. The graph illustrates the levels of apoptosis in HNSCC cells (UM-SCC-17B) treated with two different doses of Nisin ZP and Nisin AP (Handary, Belgium; www.handary.com) with and without Cisplatin. Controls were treated with media alone. Comparisons between groups show significant differences,* p<0.05 nisin compared to control, # p<0.001 Nisin plus Cisplatin compared to Nisin alone.
Journal Reference
Nisin ZP, a Bacteriocin and Food Preservative, Inhibits Head and Neck Cancer Tumorigenesis and Prolongs Survival
PLoS One. 2015;10(7):e0131008.
Kamarajan P1, Hayami T2, Matte B1, Liu Y1, Danciu T1, Ramamoorthy A3, Worden F4, Kapila S2, Kapila Y1.
[expand title=”Show Affiliations”]- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
- Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
- Department of Chemistry and Biophysics, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, United States of America.
- Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Abstract
The use of small antimicrobial peptides or bacteriocins, like nisin, to treat cancer is a new approach that holds great promise. Nisin exemplifies this new approach because it has been used safely in humans for many years as a food preservative, and recent laboratory studies support its anti-tumor potential in head and neck cancer. Previously, we showed that nisin (2.5%, low content) has antitumor potential in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. The current studies explored a naturally occurring variant of nisin (nisin ZP; 95%, high content) for its antitumor effects in vitro and in vivo. Nisin ZP induced the greatest level of apoptosis in HNSCC cells compared to low content nisin. HNSCC cells treated with increasing concentrations of nisin ZP exhibited increasing levels of apoptosis and decreasing levels of cell proliferation, clonogenic capacity, and sphere formation. Nisin ZP induced apoptosis through a calpain-dependent pathway in HNSCC cells but not in human oral keratinocytes. Nisin ZP also induced apoptosis dose-dependently in human umbilical vein endothelial cells (HUVEC) with concomitant decreases in vascular sprout formation in vitro and reduced intratumoral microvessel density in vivo. Nisin ZP reduced tumorigenesis in vivo and long-term treatment with nisin ZP extended survival. In addition, nisin treated mice exhibited normal organ histology with no evidence of inflammation, fibrosis or necrosis. In summary, nisin ZP exhibits greater antitumor effects than low content nisin, and thus has the potential to serve as a novel therapeutic for HNSCC.
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