Nisin, a bacteriocin and commonly used food preservative, may serve as a novel potential therapeutic for treating head and neck squamous cell carcinoma (HNSCC), as it induces preferential apoptosis, cell cycle arrest, and reduces cell proliferation in HNSCC cells, compared with primary keratinocytes. Nisin also reduces HNSCC tumorigenesis in vivo. Mechanistically, nisin exerts these effects on HNSCC, in part, through CHAC1, a proapoptotic cation transport regulator, and through a concomitant CHAC1-independent influx of extracellular calcium. In addition, although CHAC1 is known as an apoptotic mediator, its effects on cancer cell apoptosis have not been examined. Our studies are the first to report CHAC1's new role in promoting cancer cell apoptosis under nisin treatment. These data support the concept that nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC, and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated.

Cancers may contain a small sub-population of uniquely tumorigenic cells that exhibit self-renewal and multipotency, i.e. cancer stem cells (CSC). These cells reside in invasive fronts in close proximity to blood vessels in many tumors, including head and neck squamous cell carcinomas (HNSCC). Recent evidence suggests that CSC resist chemotherapy and “drive” local recurrence and metastatic spread. Notably, endothelial cell-initiated signaling is critical for the survival and self-renewal of CSC and may play a role in resistance to therapy. Therefore, patients with head and neck cancer might benefit from therapies that target the CSC directly or their supportive perivascular niche.

BackgroundThe intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers.MethodsThe Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 μg/d L-selenomethionine) and vitamin E (400 IU/day all rac-α-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function.ResultsCompared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV1) or forced expiratory flow (FEF25–75). There was no evidence for a smoking by treatment interaction for FEV1, but selenium attenuated rate of decline in FEF25–75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF25–75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E.ConclusionsAmong all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF25–75, a marker of airflow.Trial registrationClinicaltrials.gov identifier: NCT00241865.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0195-5) contains supplementary material, which is available to authorized users.

Oral squamous cell carcinoma (OSCC) accounts for 50% of all oral malignancies and has a poor 5-year survival rate. Resistance to programmed cell death or apoptosis contributes to oral cancer progression and formation of aggressive tumors. Finding novel therapies that promote apoptosis is crucial for mitigating oral cancer. While bacteriocins, like nisin, prevent bacterial growth in foods, they have only recently been tested for prevention of cancer cell growth. Because nisin produces cell membrane pores, it changes ionic gradients within cells, leading to a net influx of calcium. This calcium increase may play a significant role in the induction of apoptosis and reduction in proliferation in cancer cells. We hypothesized that nisin, a bacteriocin and commonly used food preservative, has potential to serve as a novel therapeutic for treating OSCC. In vitro experiments to examine the effect of nisin on OSCC cells include: cell proliferation and apoptosis assays, immunoblotting, flow cytometry to determine cell cycle status, calcium influx assays, transfections to examine the mechanism of nisin's effects. An orthotopic oral cancer mouse model was used to study the inhibitory effect of nisin on OSCC tumor growth in vivo. Nisin induces apoptosis and reduces proliferation of OSCC cells with a concomitant influx of extracellular calcium compared to primary oral keratinocytes. A concomitant influx of extracellular calcium and cell cycle arrest at the G2 check point followed nisin treatment. Nisin inhibited cell proliferation of OSCC cells by decreasing phosphorylation of cdc-2 and cyclin B, key modulators of the G2 phase of the cell cycle. In affymetrix gene array data, the most highly upregulated gene under nisin treatment conditions was ChaC1, a cation transport regulator activated by oxidized phospholipids that enhances apoptosis. Since nisin is known to preferentially interact with membrane phospholipids, ChaC1 is a likely nisin target. Nisin induces preferential apoptosis and decreased cell proliferation of OSCC cells compared to primary keratinocytes, likely due to differences in their membrane phospholipid composition that lead to greater increases in intracellular calcium and activation of ChaC1 in OSCC cells. Downregulation of Chac1 increased OSCC cell growth by increasing cdc-2 phosphorylation and cyclin B expression following nisin treatment. Mice tolerated high nisin doses well without compromising survival. Nisin administration reduced OSCC tumor burden in mice compared to double-distilled-water treated controls. These studies demonstrate that nisin suppresses OSCC cell and tumor growth in vitro and in vivo by promoting OSCC cell apoptosis, cell cycle arrest, and inhibiting cell proliferation. Increases in intracellular calcium potentially mediate this mechanism. These findings help establish baseline information regarding potential therapeutic use of nisin for OSCC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2011-4601