Modifying effects of menthol against benzo(a)pyrene‐induced forestomach carcinogenesis in female Swiss mice

Abstract

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon widespread in the environment and closely associated to tobacco use, which is an important risk factor for highly incident stomach cancer. Menthol, a monoterpene extracted from Mentha genus species, has multiple biological properties, including anti‐inflammatory and gastroprotective properties, but its effects on carcinogenesis are still to be fully understood. Thus, we evaluated the modifying effects of Ment against BaP‐induced forestomach carcinogenesis. Female Swiss mice received BaP by intragastrical (i.g.) administration (50 mg/kg of body weight [b wt], 2×/week), from weeks 1–5 weeks. Concomitantly, mice received Menthol at 25 (Ment25) or 50 (Ment50) mg/kg b wt (i.g, 3×/week). Animals were euthanized at weeks 5 (n = 5 mice/group) or 30 (n = 10 mice/group). At week 5, both Ment doses reduced peripheral leukocyte blood genotoxicity 4 h after the last BaP administration, but only Ment50 attenuated this biomarker 8 h after the last BaP administration. In accordance to these findings, both Ment interventions attenuated BaP‐induced increase in the percentage of H2A.X‐positive forestomach epithelial cells. Moreover, Ment50 reduced cell proliferation and apoptosis (i.e., Ki‐67 and caspase‐3, respectively) in forestomach epithelium but exerted no significant effects on NFκB, and Nrf2 protein levels. At week 30, Ment50 reduced by ~55% the incidence of BaP‐induced forestomach diffuse hyperplasia and multiplicity of forestomach tumors (squamous cell papillomas and carcinomas). Our findings indicate that Ment50, administered during initiation phase, attenuates forestomach carcinogenesis by reducing early genotoxicity, cell proliferation, and apoptosis induced by BaP.

Menthol Pretreatment Alleviates Campylobacter jejuni-Induced Enterocolitis in Human Gut Microbiota-Associated IL-10−/− Mice

“…The anti-inflammatory effects of exogenous menthol were also evident on the microscopic level, given that treated animals displayed diminished pathogen-induced colonic epithelial apoptosis (Figure 4C). In support, previous in vivo studies reported potent anti-apoptotic effects upon menthol treatment, given decreases in pro-apoptotic molecules such as cleaved caspase-3 and Bax protein and/or increases in anti-apoptotic molecules including Bcl-2 and HSP-70 [32,33,46,47]. The dampened apoptotic responses upon C. jejuni infection were accompanied by lower numbers of macrophages and monocytes in the colonic mucosa in menthol-pretreated mice on day 6 p.i.…”

Menthol: An underestimated anticancer agent

“…In another study, female Swiss mice were administered benzo(a) pyrene to induce cancer. Treatment with menthol (50 mg/kg of body weight, twice a week) at the initial stage of benzo(a)pyrene administration showed a reduced incidence of precancerous gastric lesions owing to reduced genotoxicity, reduced cell proliferation, and regulated apoptosis (Santo et al, 2021).…”

“…Particularly, in vitro experiments have revealed the anti-proliferative potential of menthol against various tumor cell lines (Fatima et al, 2021). Mechanistically, menthol induces apoptosis in cancer cells, indicating its role as an anticancer agent (Beck et al, 2007) against a variety of cancers, such as prostate cancer (Kim et al, 2009), colon cancer (Faridi et al, 2016), skin cancer (Fatima et al, 2021), uveal melanoma (Walcher et al, 2018), pancreatic ductal Frontiers in Pharmacology frontiersin.org adenocarcinoma (Cucu et al, 2014), gastric cancer (Santo et al, 2021), liver cancer (Lin et al, 2001), leukemia (Lu et al, 2007a), and bladder cancer (Li et al, 2009) (Figure 2). Irrespective of these data, the anticancer properties of menthol have not been sufficiently implemented in clinical practice.…”