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The inflammation-reducing compatible solute ectoine does not impair the cytotoxic effect of ionizing radiation on head and neck cancer cells.

ABSTRACT: Ectoine is a natural protectant expressed by halophile bacteria to resist challenges of their natural environments, such as drought, heat or high salt concentrations. As a compatible solute, ectoine does not interfere with the cell's metabolism even at high molar concentrations. External application of ectoine results in surface hydration and membrane stabilization. It can reduce inflammation processes and was recently tested in a pilot study for the prevention and treatment of chemotherapy-induced oral mucositis. Oral mucositis is especially frequent and severe in patients with head and neck squamous cell carcinoma (HNSCC), who receive radiotherapy or chemoradiation. It is extremely painful, can limit nutritional intake and may necessitate treatment interruptions, which can critically compromise outcome. As it was recently reported that in vitro ectoine has the ability to protect DNA against ionizing irradiation, it was the aim of this study to test whether ectoine may protect HNSCC cells from radiotherapy. Using HNSCC cell lines and primary human fibroblasts, we can show that in living cells ectoine does not impair DNA damage induction and cytotoxicity through ionizing radiation. We therefore conclude that testing the ectopic application of ectoine for its ability to alleviate early radiotherapy/chemoradiation-induced side effects is safe and feasible.

SUBMITTER: Rieckmann T

PROVIDER: S-EPMC6488604 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The inflammation-reducing compatible solute ectoine does not impair the cytotoxic effect of ionizing radiation on head and neck cancer cells.

Rieckmann Thorsten T Gatzemeier Fruzsina F Christiansen Sabrina S Rothkamm Kai K Münscher Adrian A

Scientific reports 20190429 1

Ectoine is a natural protectant expressed by halophile bacteria to resist challenges of their natural environments, such as drought, heat or high salt concentrations. As a compatible solute, ectoine does not interfere with the cell's metabolism even at high molar concentrations. External application of ectoine results in surface hydration and membrane stabilization. It can reduce inflammation processes and was recently tested in a pilot study for the prevention and treatment of chemotherapy-indu ...[more]

PMID: 31036876

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Project description:By using natural-abundance (13)C-nuclear magnetic resonance spectroscopy and high-performance liquid chromatography (HPLC) analysis we have investigated the types of compatible solutes that are synthesized de novo in a variety of Bacillus species under high-osmolality growth conditions. Five different patterns of compatible solute production were found among the 13 Bacillus species we studied. Bacillus subtilis, B. licheniformis, and B. megaterium produced proline; B. cereus, B. circulans, B. thuringiensis, Paenibacillus polymyxa, and Aneurinibacillus aneurinilyticus synthesized glutamate; B. alcalophilus, B. psychrophilus, and B. pasteurii synthesized ectoine; and Salibacillus (formerly Bacillus) salexigens produced both ectoine and hydroxyectoine, whereas Virgibacillus (formerly Bacillus) pantothenticus synthesized both ectoine and proline. Hence, the ability to produce the tetrahydropyrimidine ectoine under hyperosmotic growth conditions is widespread within the genus Bacillus and closely related taxa. To study ectoine biosynthesis within the group of Bacillus species in greater detail, we focused on B. pasteurii. We cloned and sequenced its ectoine biosynthetic genes (ectABC). The ectABC genes encode the diaminobutyric acid acetyltransferase (EctA), the diaminobutyric acid aminotransferase (EctB), and the ectoine synthase (EctC). Together these proteins constitute the ectoine biosynthetic pathway, and their heterologous expression in B. subtilis led to the production of ectoine. Northern blot analysis demonstrated that the ectABC genes are genetically organized as an operon whose expression is strongly enhanced when the osmolality of the growth medium is raised. Primer extension analysis allowed us to pinpoint the osmoregulated promoter of the B. pasteurii ectABC gene cluster. HPLC analysis of osmotically challenged B. pasteurii cells revealed that ectoine production within this bacterium is finely tuned and closely correlated with the osmolality of the growth medium. These observations together with the osmotic control of ectABC transcription suggest that the de novo synthesis of ectoine is an important facet in the cellular adaptation of B. pasteurii to high-osmolarity surroundings.

Project description:Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. Here, we report that exosomes are able to modify the radiation response of the head and neck cancer cell lines BHY and FaDu. Exosomes were isolated from the conditioned medium of irradiated as well as non-irradiated head and neck cancer cells by serial centrifugation. Quantification using NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response of other cells the exosomes were transferred to non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes isolated from both irradiated and non-irradiated cells by irradiated recipient cells compared to non-irradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6, 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate that radiation influences both the abundance and action of exosomes on recipient cells. Exosomes transmit prosurvival effects by promoting the proliferation and radioresistance of head and neck cancer cells. Taken together, this study indicates a functional role of exosomes in the response of tumor cells to radiation exposure within a therapeutic dose range and encourages that exosomes are useful objects of study for a better understanding of tumor radiation response.

Project description:BackgroundCompatible solutes are natural substances that are known to stabilize cellular functions. Preliminary ex vivo and in vivo studies demonstrated that the compatible solute ectoine restores natural apoptosis rates of lung neutrophils and contributes to the resolution of lung inflammation. Due to the low toxicity and known compatibility of the substance, an inhalative application as an intervention strategy for humans suffering from diseases caused by neutrophilic inflammation, like COPD, had been suggested. As a first approach to test the feasibility and efficacy of such a treatment, we performed a population-based randomized trial.ObjectiveThe objective of the study was to test whether the daily inhalation of the registered ectoine-containing medical device (Ectoin® inhalation solution) leads to a reduction of neutrophilic cells and interleukin-8 (IL-8) levels in the sputum of persons with mild symptoms of airway disease due to lifelong exposure to environmental air pollution.MethodsA double-blinded placebo-controlled trial was performed to study the efficacy and safety of an ectoine-containing therapeutic. Prior to and after both inhalation periods, lung function, inflammatory parameters in sputum, serum markers, and quality-of-life parameters were determined.ResultsWhile the other outcomes revealed no significant effects, sputum parameters were changed by the intervention. Nitrogen oxides (nitrate and nitrite) were significantly reduced after ectoine inhalation with a mean quotient of 0.65 (95% confidence interval 0.45-0.93). Extended analyses considering period effects revealed that the percentage of neutrophils in sputum was significantly lower after ectoine inhalation than in the placebo group (P=0.035) even after the washout phase.ConclusionThe current study is the first human trial in which the effects of inhaled ectoine on neutrophilic lung inflammation were investigated. Besides demonstrating beneficial effects on inflammatory sputum parameters, the study proves the feasibility of the therapeutic approach in an aged study group.

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The inflammation-reducing compatible solute ectoine does not impair the cytotoxic effect of ionizing radiation on head and neck cancer cells.

Publications

The inflammation-reducing compatible solute ectoine does not impair the cytotoxic effect of ionizing radiation on head and neck cancer cells.

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