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. 2020 Mar 13;41(1):91-99.
doi: 10.1093/carcin/bgz158.

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

Alberto Izzotti  1   2 , Roumen Balansky  3 , Rosanna T Micale  1 , Alessandra Pulliero  1 , Sebastiano La Maestra  1 , Silvio De Flora  1
Affiliations

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

Alberto Izzotti et al. Carcinogenesis. .

Abstract

Chronic inflammation plays a crucial role in the carcinogenesis process and, in particular, in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods.

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Figures

Figure 1.
Figure 1.
Examples of 32P autoradiographs obtained by testing the lung DNA from mice, either unexposed (Sham) or exposed to MCS and treated with licofelone. The framed areas correspond to the DRZ in MCS-exposed mice where the radioactive signal was measured (see the results in Table 1).
Figure 2.
Figure 2.
Global expression of 1135 pulmonary miRNAs in the mice belonging to 4 experimental groups, including sham-exposed mice, mice receiving licofelone with the diet for 6 weeks, starting after weanling, and mice exposed to MCS for 10 weeks, starting after birth, either untreated or treated with licofelone. (A) Hierarchical cluster analysis (HCA). Within each column, the expression of the analyzed lung miRNAs is represented on a relative color scale (blue, low; yellow, medium; orange to red, high). (B) Bidimensional principal component analysis (PCA) showing the allocation of the average expression of pulmonary miRNAs in the mice belonging to four experimental groups.
Figure 3.
Figure 3.
(A–C) Scatter-plot analyses comparing the expression of pulmonary miRNAs in sham-exposed mice vs. mice treated with licofelone (A), MCS-exposed mice vs. sham-exposed mice (B), and MCS-exposed mice treated with licofelone versus MCS-exposed mice in the absence of the drug (C). Each dot represents a miRNA, whose expression intensity can be inferred from the position in the x and y axes, according to a color scale (blue, low; yellow, medium; orange to red, high). The diagonal belts indicate the 2-fold variation interval. Symbols falling in the upper area denote miRNA upregulation, and those falling in the lower area denote miRNA downregulation by licofelone. (D–F) Volcano-plot analyses comparing the expression of pulmonary miRNAs in sham-exposed mice versus mice treated with licofelone (D), MCS-exposed mice versus sham-exposed mice (E), and MCS-exposed mice treated with licofelone versus MCS-exposed mice in the absence of the drug (F). The two green vertical lines indicate the 2-fold variation interval, and the horizontal green line indicates the P < 0.05 threshold. miRNAs falling outside these intervals are highlighted in red color.
Figure 4.
Figure 4.
Evaluation of miR-30b expression by qPCR. Amplification curves are reported for each one of the four experimental conditions. The column graph quantifies the level of miR-30b expression.
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