Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention.

Head and neck squamous cell carcinoma (HNSCC) is a significant public health problem, with a need for novel approaches to chemoprevention and treatment. Preclinical models that recapitulate molecular alterations that occur in clinical HNSCC patients are needed to better understand molecular and immune mechanisms of HNSCC carcinogenesis, chemoprevention, and efficacy of treatment. We optimized a mouse model of tongue carcinogenesis with discrete quantifiable tumors via conditional deletion of Tgfßr1 and Pten by intralingual injection of tamoxifen. We characterized the localized immune tumor microenvironment, metastasis, systemic immune responses, associated with tongue tumor development. We further determined the efficacy of tongue cancer chemoprevention using dietary administration of black raspberries (BRB). Three Intralingual injections of 500 µg tamoxifen to transgenic K14 Cre, floxed Tgfbr1, Pten (2cKO) knockout mice resulted in tongue tumors with histological and molecular profiles, and lymph node metastasis similar to clinical HNSCC tumors. Bcl2, Bcl-xl, Egfr, Ki-67, and Mmp9, were significantly upregulated in tongue tumors compared to surrounding epithelial tissue. CD4+ and CD8 + T cells in tumor-draining lymph nodes and tumors displayed increased surface CTLA-4 expression, suggestive of impaired T-cell activation and enhanced regulatory T-cell activity. BRB administration resulted in reduced tumor growth, enhanced T-cell infiltration to the tongue tumor microenvironment and robust antitumoral CD8+ cytotoxic T-cell activity characterized by greater granzyme B and perforin expression. Our results demonstrate that intralingual injection of tamoxifen in Tgfßr1/Pten 2cKO mice results in discrete quantifiable tumors suitable for chemoprevention and therapy of experimental HNSCC.

Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.

Yes-associated protein 1 (YAP1) and its paralogue PDZ-binding motif (TAZ) play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29 049 low-molecular-weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS-induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT-treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS-YAP pathway driving tumor cell growth and so could be a potent anticancer drug.

Can propranolol act as a chemopreventive agent during oral carcinogenesis? An experimental animal study.

The multistep process of oral carcinogenesis provides a biological rationale for the use of chemoprevention in individuals at increased risk of developing oral cancer. We aimed to determine if low doses of propranolol can prevent the development of oral cancer using a tobacco-relevant and p53-associated animal model of cancer initiation. Twenty-six Wistar rats were randomly allocated into two groups, vehicle, and propranolol. All animals received 4-nitroquinoline N-oxide (4NQO) at 25 ppm diluted in the drinking water for 20 weeks. Animals from the propranolol group received propranolol (0.1 mg/kg) 5 days per week by gavage for 18 weeks. The clinical analysis was performed by measuring the area of the lesion and assessment of scores based on lesion appearance (papule; plaque; nodule or ulcerated). Histopathological analysis was performed to determine the presence of epithelial dysplasia or invasive squamous cell carcinoma (SCC). The average lesion area in 4NQO + vehicle and in 4NQO + propranolol groups were 0.20 and 0.28 mm2, respectively (P = 0.53). The percentage of cases clinically graded as papules, thick plaques, nodular areas, and ulcerated lesions was similar between groups (P = 0.94). Histopathological diagnosis also did not differ between groups (P = 0.65), with 54.5 and 70% of cases being diagnosed as SCC in 4NQO and in 4NQO + propranolol groups, respectively. In conclusion, daily doses propranolol at 0.1 mg/kg were not as effective as a chemopreventive therapy in an animal model of 4NQO-induced carcinogenesis.

Protective and therapeutic effects of pyrrolidine dithiocarbamate in a rat tongue cancer model created experimentally using 4-nitroquinoline 1-oxide.

BACKGROUND: Tongue tumors, which are oropharyngeal tumors, are increasing in frequency. Pyrrolidine dithiocarbamate (PDTC) is a powerful antioxidant and antitumoral agent. OBJECTIVES: To evaluate the protective and therapeutic effects of PDTC in a tongue cancer model induced with 4-nitroquinoline 1-oxide (4-NQO). MATERIAL AND METHODS: We included 40 rats in the trial and assigned them randomly to 5 groups. Group 1 (cancer, n = 7): 4-NQO (0-12 weeks); group 2 (protection, n = 8): 4-NQO (0-12 weeks) + PDTC (300 mg/kg/day, 0-12 weeks); group 3 (therapy-high dose, n = 10): 4-NQO (0-12 weeks) + PDTC (600 mg/kg/day, weeks 12-30); group 4 (therapy-low dose, n = 10): 4-NQO (0-12 weeks) + PDTC (300 mg/kg/day, weeks 12-30); and group 5 (control). Cardiac blood samples were taken to analyze oxidative stress parameters (total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI)). Histopathological assessment was performed under a light microscope. RESULTS: The results of the histopathological assessment showed that the model we used in group 1 was successful, which was consistent with the literature. The PDTC dose administered in group 2 could not prevent tumor formation. Group 3 demonstrated that PDTC in high doses is effective as a therapeutic agent. Group 4 indicated that PDTC in low doses has no therapeutic effect. The results of the biochemical assessment showed that in group 3, TOS and OSI values were significantly lower than in groups 1, 2 and 4. No significant difference was found in the TOS and OSI values between groups 5 and 3. CONCLUSIONS: Our study demonstrated histopathologically that in an experimentally generated tongue cancer model, application of 600 mg/kg/day of PDTC led to a significant reduction in the size of the tumor. This was supported by the biochemical parameters.

Analysis of the Filipinos' Interest in Searching Online for Oral Cancer.

Objective: This study analyzed the health-seeking behavior of Filipinos using Google Trends tool to quantify relative search volume by term . Oral cancer, mouth cancer, tongue cancer, gum cancer, and lip cancer were used as predetermined search terms. Material and method: Comma-separated values file containing relative search volumes of search trends pertaining to oral cancer from 2009 to 2019 were assessed. Brown-Forsythe one-way ANOVA was used to measure differences with respect to oral cancer across different years and months. Two-way repeated measures ANOVA was applied to detect differences regarding mouth cancer, tongue cancer, gum cancer, and lip cancer across the years. Time series models were fitted and used to forecast search interests. Results: The results revealed that interest in oral cancer was significantly higher in 2019 (43.75±5.5, p<0.05) compared to 2009 (29.0 ± 6.7). In terms of months, searches were higher in February (45.0 ± 6.6) compared to May (24.8 ± 3.4, p=0.015), June (25.3 ± 4.4, p=0.020), and December (26.5 ± 4.0, p=0.038). Search interests for gum cancer and lip cancer remained significantly lower from 2011 to 2019, and tongue cancer from 2016 to 2018 but approximated mouth cancer in 2019. The forecast showed that mouth cancer (31.67%), tongue cancer (23.75%), and lip cancer (3.83%) would fluctuate through time pass, while gum cancer (8%) would remain steady in 2020. Conclusion: Health-seeking behavior through search trends showed an increased interest in oral cancer in 2019 and during February. It was anticipated that search interests would fluctuate in 2020, but at the end of the year would decrease for mouth cancer and tongue cancer, increase for lip cancer, and remain steady for gum cancer.

A global epidemic increase of an HPV-induced tonsil and tongue base cancer - potential benefit from a pan-gender use of HPV vaccine.

In 2007, human papillomavirus (HPV) type 16 was finally recognized as a risk factor, besides smoking and alcohol, for oropharyngeal squamous cell carcinoma (OPSCC), including tonsillar squamous cell carcinoma (TSCC), by the International Agency for Research against Cancer. Just before, in 2006, the Food and Drug Administration had approved Gardasil, the first vaccine against HPV16, 18, 6 and 11, for preventive vaccination women against cervical cancer. Concurrently, some Western countries, where smoking was decreasing, disclosed an epidemic increase in the incidence of OPSCC, especially of TSCC and base of tongue cancer (BOTSCC), together accounting for 80-90% of all OPSCCs, and mainly affecting men. The epidemic was later revealed to be due to a rise in HPV-positive cases, and scientists in the field suggested HPV vaccination also of boys. Globally, there are roughly 96 000 incident OPSCC cases/year of which 20-24% are caused by HPV, thereby accounting for around 22 000 OPSCC cases annually. Of these cases, 80-90% are due to HPV16 infection and would be prevented with the presently registered HPV vaccines. In Western countries, such as Sweden (with almost 400 TSCC and BOTSCC cases per year) and the United States, HPV prevalence in OPSCC is higher and around 70%. HPV vaccination of girls has been initiated in many countries, and the vaccines have been efficient and their side effects limited. HPV vaccination of boys has, however, been the exception, but should definitely not be delayed any further. It would benefit both girls and boys directly, and result in better and more robust herd immunity. Today, we have the possibility to eliminate several high-risk HPV types in the younger generations and avoid more than 600 000 cancer cases annually worldwide, and this possibility should be embraced by offering global pan-gender HPV vaccination.

Protective effects of purple carrot extract (Daucus carota) against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide.

The aim of this study was to evaluate the chemopreventive potential of purple carrot extract following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO). For this purpose, histopathological analysis, proliferative status, antioxidant activity and inflammatory status were investigated in this setting. A total of 20 male rats were distributed into four groups as follows (n = 5 per group): Group 1-free access to water and commercial diet for 12 weeks; Group 2-received 4NQO at 50 ppm dose in drinking water daily and commercial diet for 12 weeks; Group 3-free access to water and received diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks; and Group 4-received 4NQO at 50 ppm dose in drinking water daily and diet supplemented with purple carrot extract (0.1 g/kg) for 12 weeks. Histopathological analysis revealed that animals treated with purple carrot extract reduced the oral lesions such as dysplasia and squamous cell carcinoma. Animals with oral pre-neoplastic lesions and treated with purple carrot extract decreased ki-67 and 8-OHdG immunoexpression. Moreover, pNFκBp50 and MyD88 protein expressions were decreased after purple carrot treatment associated or not with 4NQO exposure. SOD-Mn mRNA levels increased with treatment with purple carrot extract as well. In conclusion, our results demonstrated that purple carrot extract was able to protect oral lesions induced by 4NQO in Wistar rats as a result of antioxidant activity, anti-inflammatory potential and antiproliferative and antimutagenic actions.

E3 ubiquitin ligase, RNF139, inhibits the progression of tongue cancer.

BACKGROUND: Tongue cancer is still one of the leading causes of mortality around the world. Recently, the ubiquitin system has been established as a critical modulator of tumors. In order to find the oral cancer related E3 ubiquitin ligases, we screened the human E3 ubiquitin ligase library and found that RING finger protein 139 (RNF139) regulated the biological behavior of tongue cancer cells. METHODS: MTT assay was used to analyze the cell viability changes of tongue cancer SCC9 and SCC25 cells caused by RNF139. The invasion ability of SCC9 and SCC25 cells with or without the knockdown of RNF139 was evaluated through transwell assay. The immunoblotting was recruited to determine the expression level of RNF139 in human tongue cancer tissues and para-carcinoma tissues. The effect of RNF139 on tumorigenicity of tongue cancer cells was analyzed by xenograft model on immunodeficient Balb/c nude mice. RESULTS: Overexpression of RNF139 inhibits the viability of tongue cancer cells since day 2. The colony formation ability of SCC9 and SCC25 cells was also decreased with the overexpression of RNF139. Knockdown of RNF139 significantly promoted the invasion ability of SCC9 and SCC25 cells. Furthermore, knockdown of RNF139 also induced the activation of AKT signaling pathway. While human tongue cancer tissues had low expression of RNF139. In nude mice, knockdown of RNF139 promoted the tumorigenicity of the SCC25 cells. CONCLUSIONS: Our data establish a role for RNF139 in regulating the progression of tongue cancer.

Geraniol attenuates 4NQO-induced tongue carcinogenesis through downregulating the activation of NF-κB in rats.

Geraniol, an acyclic monoterpene found in lemon grass and aromatic herb oil, has been shown to exert antitumor and antioxidant activities against various cancer types. The objective of this study was to investigate the potential chemoprotective role of geraniol against 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis in male Wistar rats and furthermore to study anti-inflammatory mechanisms of action through possible NF-κB signaling. 4NQO was administered to rats at the dose of 50 ppm through drinking water to induce tongue cancer in 20 weeks. 4NQO provoked inflammation by upregulating the expressions of the p65 subunit nuclear factor kappa-ß (NF-κB) in the nucleus, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, staining for immature and mature mast cells in cancer niche by toluidine blue staining and alcian blue-safranin staining showed more accumulation. Co-treatment of geraniol 200 mg/kg b.w. showed a significant decrease in the level of p65 NF-κB in the nucleus, and this might be due to the inhibition of NF-κB activation/translocation into nucleus, which was further confirmed by decreased immature and mature mast cell density and the expression of inflammatory downstream mediators such as TNF-α, IL-1ß, COX-2, and iNOS. Collectively, our results suggested that geraniol as a potential anti-inflammatory agent having the capability to obstruct 4NQO initiated NF-κB activation and modulated the expression of inflammatory mediators.

Espinalioma de lengua: informe de un caso clínico / Tongue spinalioma. clinical case report

Objetivos: concientizar sobre la importancia de la consulta estomatológica y educar en la autodetección de lesiones facultativamente cancerizables. Caso clínico: paciente con antecedentes traumáticos locales de larga data, producidos por piezas dentarias con bordes filosos, obturaciones desbordantes y el consumo de tabaco, factores predisponentes e incidentes en el desencadenamiento de la lesión neoplásica. Conclusión: el caso presentado pone en evidencia las deficientes medidas de prevención primaria y la falta de acciones conducentes a la práctica de autoevaluaciones orales periódicas.

Aim: To raise awareness about the importance of pathology consultation and patient education in self detection of potentially cancerous lesions. Clinical case: We report the case of a patient with along history of local traumatisms generated by tooth lesions with sharp edges, over contoured restorations and tobacco consumption, all of which are considered risk factors in the generation of neoplasic processes. Conclusion: The case that is reported shows lack of useof primary preventive and self detections conducts that could prevent the development of cancerous lesions.

Is an Elective Neck Dissection Necessary for All Cases of N0 Oral Squamous Cell Carcinoma? -Elective Neck Dissection may be Performed for Tongue Cancer with Tumor Thickness More than 4 mm.

We investigated whether neck dissection should be performed to prevent T1-2N0M0 tongue cancer by using the Weiss and colleague's decision tree method. The results showed that preventive neck dissection should not be recommended for T1-2N0M0 tongue cancer. However, preventive neck dissection is a suitable approach when treating tongue cancer tumors with a thickness of ≥ 4 mm.

[PAPILLOMAVIRUS INFECTION: PRINCIPLE CHARACTERISTICS, CLINICAL MANIFESTATIONS, VACCINE PROPHYLAXIS].

Papillomaviruses are a large and diverse group of viruses. It includes approximately 200 fully described types that have been detected in humans. Human papilloma viruses (HPV) are etiologic agents during various, benign and malignant lesions of mucous membrane and skin epithelium. Very importantly, persistent HPV infection of certain types is a leading cause of carcinoma of uterine cervix, penis, vulva; vagina, anal canal and fauces (including tongue base and tonsils). HPV infection prophylaxis is the best means to control HPV-conditioned diseases, and vaccination, as had been demonstrated, --the most effective method of its prophylaxis. In this paper principle characteristics and clinical manifestations of papillomavirus infection, as well as effectiveness of vaccination against HPV are examined.

Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice.

The aim of this study is to understand the molecular mechanisms of N-nitrosodiethylamine (NDEA) induced multi-organ carcinogenesis in tongue and liver of the same mouse and restriction of carcinogenesis by Epigallocatechin gallate (EGCG) and Theaflavin (TF), if any. For that purpose, cellular proliferation/apoptosis, prevalence of CD44 positive stem cell population and expressions of some key regulatory genes of self renewal Wnt and Hedgehog (Hh) pathways and some of their associated genes were analyzed in the NDEA induced tongue and liver lesions in absence or presence of EGCG/TF. Chronic NDEA exposure in oral cavity could decrease mice body weights and induce tongue and liver carcinogenesis with similar histological stages (severe dysplasia up to 30thweeks of NDEA administration). Increasing mice body weights were seen in continuous and post EGCG/TF treated groups. EGCG/TF treatment could restrict both the carcinogenesis at similar histological stages showing potential chemopreventive effect in continuous treated groups (mild dysplasia) followed by pre treatment (moderate dysplasia) and therapeutic efficacy in post treated groups (mild dysplasia) up to 30thweek. The mechanism of carcinogenesis by NDEA and restriction by the EGCG/TF in both tongue and liver were similar and found to be associated with modulation in cellular proliferation/apoptosis and prevalence of CD44 positive population. The up-regulation of self renewal Wnt/ß-catenin, Hh/Gli1 pathways and their associated genes Cyclin D1, cMyc and EGFR along with down regulation of E-cadherin seen during the carcinogenesis processes were found to be modulated during the restriction processes by EGCG/TF.

Antioxidant activity of apple extract protects against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide.

Several studies have shown that apple (Malus sp.) has many components able to exert chemopreventive activity. The aim of this study was to evaluate the chemopreventive potential of apple extract following medium-term oral carcinogenesis assay induced by 4-nitroquinoline 1-oxide (4NQO) by means of histopathological analysis and gene expression of antioxidant enzymes, such as CuZnSOD, MnSOD and catalase. A total of 30 male Wistar rats were distributed into five groups, as follows (n = 6 per group): Group 1 - negative control group (non-treated group); Group 2 - received 4NQO during 8 weeks in drinking water and treated with apple extract by gavage between the 1st and 4th weeks daily (initiation phase); Group 3 - received 4NQO for 8 weeks in drinking water and treated with apple extract by gavage between the 5th and 8th weeks daily (promotion phase); Group 4 - received apple extract by gavage for eight consecutive weeks only; and Group 5 - received 4NQO for 8 weeks in drinking water daily. Histopathological analysis revealed that apple extract protect oral lesions induced by 4NQO at initiation or promotion phase. Higher gene expression of CuZnSOD and MnSOD enzymes were noticed in groups treated with apple extract as well. Taken together, our results demonstrate that the apple extract is able to modulate medium-term oral carcinogenesis assay as a result of antioxidant activity.

Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses.

Preventive measures against oral carcinogenesis are urgently warranted to lower the high morbidity and mortality associated with this malignancy worldwide. Here, we investigated the chemopreventive efficacy of grape seed extract (GSE) and resveratrol (Res) in 4-nitroquinoline-1-oxide (4NQO)-induced tongue tumorigenesis in C57BL/6 mice. Following 8 weeks of 4NQO exposure (100 µg/ml in drinking water), mice were fed with either control AIN-76A diet or diet containing 0.2% GSE (w/w) or 0.25% Res (w/w) for 8 subsequent weeks, while continued on 4NQO. Upon termination of the study at 16 weeks, tongue tissues were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for molecular targets by immunohistochemistry. GSE and Res feeding for 8 weeks, moderately decreased the incidence, but significantly prevented the multiplicity and severity of 4NQO-induced preneoplastic and neoplastic lesions, without any apparent toxicity. In tongue tissues, both 4NQO + GSE and 4NQO + Res treatment correlated with a decreased proliferation (BrdU labeling index) but increased apoptotic death (TUNEL-positive cells) as compared to the 4NQO group. Furthermore, tongue tissues from both the 4NQO + GSE and 4NQO + Res groups showed an increase in activated metabolic regulator phospho-AMPK (Thr172) and decreased autophagy flux marker p62. Together, these findings suggest that GSE and Res could effectively prevent 4NQO-induced oral tumorigenesis through modulating AMPK activation, and thereby, inhibiting proliferation and inducing apoptosis and autophagy, as mechanisms of their efficacy.

Chemopreventive effect of Mentha piperita on dimethylbenz[a]anthracene and formaldehyde-induced tongue carcinogenesis in mice (histological and immunohistochemical study).

OBJECTIVE: Cancer chemoprevention is defined as the use of chemicals or dietary components to block, inhibit, or reverse the development of cancer in normal or pre-neoplastic tissue. Mentha extract (ME) has antioxidant and antiperoxidant properties. This study was held to investigate the protective and anticancer effect of Mentha leaves aqueous extract on oral epithelium of mice tongues. DESIGN: A total of 80 Egyptian albino mice were divided into three groups. Group I served as control (not subjected to any kind of treatment), and groups II and III were subjected to two-stage chemical carcinogenesis through topical application of dimethylbenz[a]anthracene (DMBA) followed by formaldehyde on dorsal and ventral surfaces of tongues for 9 weeks. Mentha leaves extract was administrated to group III at the same time of cancer induction. Histological changes were assessed in H&E sections at 3-week intervals. The anticarcinogenic effect of Mentha piperita was tested using immunostain with anticaspase antibody. RESULTS: The oral administration of ME reduced the appearance of dysplastic cellular changes with 61% and inhibited tumor incidence with 100%. Group I showed moderate-to-strong cytoplasmic caspase expression. At 6-week interval, group II showed weak-to-moderate caspase expression, while sections from group III showed moderate-to-strong caspase expression. High significant statistical difference in the total score of caspase 3 expression was found between specimens obtained from animals sacrificed at 6 weeks in groups I, II, and III (P = 0.001**). CONCLUSION: Our study demonstrated that Mentha piperita has inhibited the initiation and promotion of oral dysplastic lesions.

Anti-tumor activity of grape juice concentrate in the rat tongue two-stage initiation-promotion protocol induced by 4-nitroquinoline 1-oxide.

The aim of this study was to evaluate the anti-tumor activity of grape juice concentrate following medium-term oral carcinogenesis assay induced by 4-nitroquinoline 1-oxide (4NQO). A total of 30 male Wistar rats were distributed into five groups, as follows (n = 6 per group): Group 1 - negative control group (non-treated group); Group 2 - received grape juice concentrate at 1% dose by gavage for eight consecutive weeks; Group 3 - received 4NQO for 8 weeks at 20 ppm dose in drinking water daily; Group 4 - received 4NQO at 20 ppm dose during 8 weeks in drinking water and treated with grape juice concentrate at 1% dose orally by gavage for first 4 weeks after 4-NQO administration; Group 5 - received 4NQO at 20 ppm dose for 8 weeks in drinking water and treated with grape juice concentrate at 1% dose orally by gavage between the 5th and 8th weeks daily. Histopathological analysis revealed a decrease in hyperplasic and dysplastic lesions in Group 4. Groups 4 and 5 showed decreased COX-2 and TNF-alpha and eNOS gene expression. Grape juice concentrate also increased SOD Cu/Zn and catalase expression. However, Ki-67 immunoexpression was reduced at the promotion step of oral carcinogenesis (G5). Taken together, our results demonstrate that grape juice concentrate modulates rat tongue carcinogenesis as a result of anti-inflammatory activity, antioxidant activity and down-regulation of oral cells proliferation.

Geraniol modulates tongue and hepatic phase I and phase II conjugation activities and may contribute directly to the chemopreventive activity against experimental oral carcinogenesis.

Xenobiotic metabolizing enzymes are chief determinants in both the susceptibility to mutagenic effect of chemical carcinogens and in the response of tumors to chemotherapy. The present study was aimed to analyze the effect of geraniol administration on the activity of phase I and phase II carcinogen metabolizing enzymes through the nuclear factor erythroid 2-related factor-2 (Nrf2) activation against 4-niroquinoline-1-oxide (4NQO) induced oral carcinogenesis. The well-known chemical carcinogen 4NQO (50 ppm) was used to induce oral carcinogenesis through drinking water for 4, 12, and 20 weeks. The degree of cancer progression at each stage was confirmed by histological examination. At the end of the experimental period, 100% tumor formation was observed in the oral cavity of 4NQO induced animals with significant (P<0.05) alteration in the status of tumor markers, tongue and liver phase I and phase II drug metabolizing enzymes indicating progression of disease. Oral administration of geraniol at the dose of 200 mg/kg b.wt., thrice a week to 4NQO induced animals was able to inhibit tumor formation and thereby delayed the progression of oral carcinogenesis by modulating tongue and liver phase I and phase II drug metabolizing enzymes, as substantiated further by the histological and transmission electron microscopic studies. Our results demonstrate that geraniol exerts its chemopreventive potential by altering activities of phases I and II drug metabolizing enzymes to achieve minimum bioactivation of carcinogen and maximum detoxification.