•CAPE sensitizes only adenocarcinoma NSCLC to irradiation.•Mechanistically CAPE affects cell cycle distribution, metabolism and NF-κB activity.•CAPE decreases radiation-induced pro-inflammatory ...markers in ex vivo lung tissue.
Lung cancers are highly resistant to radiotherapy, necessitating the use of high doses, which leads to radiation toxicities such as radiation pneumonitis and fibrosis. Caffeic Acid Phenethyl Ester (CAPE) has been suggested to have anti-proliferative and pro-apoptotic effects in tumour cells, while radioprotective anti-inflammatory and anti-oxidant effects in the normal tissue. We investigated the radiosensitizing and radioprotective effects of CAPE in lung cancer cell lines and normal tissue in vitro and ex vivo, respectively.
The cytotoxic and radiosensitizing effects of CAPE in lung cancer were investigated using viability and clonogenic survival assays. The radioprotective effects of CAPE were assessed in vitro and ex vivo using precision cut lung slices (PCLS). Potential underlying molecular mechanisms of CAPE focusing on cell cycle, cell metabolism, mitochondrial function and pro-inflammatory markers were investigated.
Treatment with CAPE decreased cell viability in a dose-dependent manner (IC50 57.6 ± 16.6 μM). Clonogenic survival assays showed significant radiosensitization by CAPE in lung adenocarcinoma lines (p < 0.05), while no differences were found in non-adenocarcinoma lines (p ≥ 0.13). Cell cycle analysis showed an increased S-phase (p < 0.05) after incubation with CAPE in the majority of cell lines. Metabolic profiling showed that CAPE shifted cellular respiration towards glycolysis (p < 0.01), together with mitochondrial membrane depolarization (p < 0.01). CAPE induced a decrease in NF-κB activity in adenocarcinomas and decreased pro-inflammatory gene expression in PCLS.
The combination of CAPE and radiotherapy may be a potentially effective approach to increase the therapeutic window in lung cancer patients.
Purpose:
To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a ...variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors.
Methods:
Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis–Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M
0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M
0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity.
Results:
After optimization, high pixel-based correlations up to R
2 = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R
2 ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M
0 differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s.
Conclusions:
It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M
0, whose optimum value differed significantly between tumor models.
Hypoxia is a common characteristic of solid tumors and is associated with poor prognosis. Positron emission tomography (PET) can visualize tumor hypoxia in a non-invasive, 3-dimensional manner and ...can be used to acquire information longitudinally. Multiple 2-nitroimidazole based PET tracers are developed, validated and quantified in the search for the ideal hypoxia tracer and several tracers have shown to reliably represent tumor hypoxia. Furthermore, multiple studies describe the prognostic value of hypoxia PET imaging and the ability to monitor hypoxia during treatment. These applications can be of great potential and their role in treatment planning and modification needs to be further assessed with respect to personalized chemoradiation therapy. In this review we focus on the tracers that were positively validated in preclinical and clinical studies and report accurate quantification and visualization of hypoxia. The characteristics of these tracers are summarized for both preclinical and clinical studies. Furthermore, the clinical applications of hypoxia PET imaging are addressed with a focus on the ability to reliably monitor tumor hypoxia during treatment and the prognostic potential. Also the feasibility studies for hypoxia guided intensity modulated radiation therapy and the patient stratification for hypoxia targeted drugs are assessed.
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