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. 2018 Sep 24;8(1):14257.
doi: 10.1038/s41598-018-32423-0.

Intranasal administration of resveratrol successfully prevents lung cancer in A/J mice

Aymeric Monteillier  1 , Aymone Voisin  1 , Pascal Furrer  1 , Eric Allémann  1 , Muriel Cuendet  2
Affiliations

Intranasal administration of resveratrol successfully prevents lung cancer in A/J mice

Aymeric Monteillier et al. Sci Rep. .

Abstract

Lung cancer is the most lethal cancer in the world. About 80% of lung cancer deaths are linked to tobacco use. As a complement to tobacco control, efficient chemoprevention strategies are needed to tackle lung cancer epidemic. Resveratrol is one of the most studied natural products, notably for its cancer chemoprevention properties. However, its low oral bioavailability has often limited the translation of in vitro activities to in vivo effects. While oral administration of resveratrol effectively inhibited colorectal carcinogenesis, it failed to protect mice from chemically-induced lung carcinogenesis. Therefore, non-invasive parenteral routes must be considered to bring resveratrol to the lungs. In the present study, intranasal administration of a concentrated formulation proved to be a valid method to expose the lungs to a sufficient amount of resveratrol. This formulation was administered three times a week for 25 weeks to A/J mice having 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone-induced lung carcinogenesis. Resveratrol-treated mice showed a 27% decrease in tumour multiplicity, with smaller tumours, resulting in 45% decrease in tumour volume/mouse. In vitro investigations highlighted apoptosis as a potential mechanism of action. This study presents an effective way to overcome resveratrol low oral bioavailability, encouraging a reevaluation of its use in future clinical trials.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
RES content over time in lung tissue (a) and in the blood (b) after a single intranasal administration of 1.2 mg/mouse RES (n = 3 for each time point).
Figure 2
Figure 2
Inhibition of NNK-induced lung carcinogenesis by RES treatment. (a) Experimental design of the study. (b) Mice were randomized into four groups and received the following treatments: Group 1 (NNK−/RES−); Group 2 (NNK+/RES−); Group 3 (NNK+/RES+); Group 4 (NNK−/RES+). Tumour multiplicity in groups 1–4. Significant reduction was observed in group 3 compared to group 2 (P = 0.0472) (c) Tumour size in groups 2 and 3. Significant reduction was observed in tumours with 0.5–1 mm (P = 0.0324) and >1 mm (P = 0.0128) diameter (d) Estimated total tumour volume in groups 2 and 3, calculated with the formula V = (D ∗ d ∗ 0.2 ∗ π)/6). Significant reduction was observed in group 3 (P = 0.0029) (e) Tumour incidence. (f) Representative images of lungs from mice of groups 2 and 3. Visible tumours are pointed by red arrows. (g) Body weight as a function of time in each group. No obvious sign of toxicity was observed in RES treated groups.
Figure 3
Figure 3
NNK did not induce NF-κB activation in vivo. Immunohistochemistry on samples of lung tumours from groups 2 and 3 with NF-κB p65 (stained in green) and DAPI (stained in blue).
Figure 4
Figure 4
RES induced γ-H2AX protein expression in A549 cells. Immunocytochemistry analyses (a) and quantification (b) of γ-H2AX marked A549 cells following treatment with DMSO (0.05%), NNK alone, or NNK + RES. Significant γ-H2AX induction was observed after treatment with NNK + RES 40 µM (P = 0.0129), NNK + RES 80 µM (P = 0.0003), and NNK + RES 160 µM (P = 0.0001) compared to DMSO control (n = 3). (c) Cropped western blot analyses of γ-H2AX expression in A549 cells following DMSO (0.05%), NNK alone, or NNK + RES treatment. Full lengths blots/gels are presented in Supplementary Fig. S1.
Figure 5
Figure 5
RES induced apoptosis in A549 cells. Apoptosis measurement using Annexin V/PI in A549 cells treated with NNK + RES or RES alone (n = 3). Significant increase in apoptotic cells was observed after treatment with NNK + RES 40 µM (P = 0.0001), NNK + RES 80 µM (P = 0.0001), NNK + RES 160 µM (P = 0.0001), RES 40 µM (P = 0.0003), RES 80 µM (P = 0.0001), and RES 160 µM (P = 0.0001) compared to DMSO control.
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