Dimethylbenzanthracene Research Articles

Design and development of novel fasudil derivatives as potent antibreast cancer agent that improves intestinal flora and intestinal barrier function in rats.

This study was conducted to develop novel fasudil derivatives after incorporation of substituted thiazoles as potent anti-breast cancer (BC) agents. The compounds were developed using a facile synthetic route in excellent yields. The entire set of developed compounds was tested for inhibitory activity against rho-associated coiled-coil kinase (ROCK; ROCK1 and ROCK2) kinase, where they exhibit potent and selective inhibition of ROCK1 as compared to ROCK2. The most potent ROCK2 inhibitor, compound 6h significantly inhibited the viability of BC cells (MCF-7). It also causes inhibition of migration and invasion of MCF-7 cells. Moreover, the anti-BC activity of compound 6h was studied in 7,12 dimethyl Benz(a)anthracene (DMBA)-induced BC in female Sprague Dawley rats. Results suggest that it causes significant improvement in the bodyweight of the animals with a reduction in oxidative stress in the liver and mammary tissues of rats. It showed improvement in the intestinal barrier function of rats by restoring the level of Diamine oxidase, d-lactate, and endotoxin. In western blot analysis, it showed improvement in (ZO-1), occludin, and claudin-1 in the colon tissue of the rat as compared to the DMBA group. Our study demonstrated the development of the novel class of fasudil derivatives potent anti-BC agent that improves intestinal flora and intestinal barrier function in rats.

Biological Effects of DMBA and Lagenaria siceraria:2: Modulatory Role of Lagenaria siceraria on The Ileum of Females Swiss Albino Mice Induced by The Possible carcinogenic effect of DMBA

Background: Cancer is constituted as the most famous fatal disease among human-being. DMBA is a common carcinogen and immunosuppressant and experimentally used for the induction of mutations via the creation of DNA adducts. Aim: Evaluation of the therapeutic effect of Lagenaria siceraria on 9,10 dimethyl-1, 2-benzanthracene (DMBA)-induced changes. Materials and Methods: A total number of thirty adult female albino rats within average age 3 months classified into 3 groups as follow: Group1 is designated as control. Group 2 was subcutaneously injected with a single dose of DMBA (10 mg/ 100 g b. wt) and after 90 days, animals have received a daily injection of distilled water for 30 days. Group 3 was subcutaneously mice were injected with a single dose of DMBA and after 90 days, mice were received morning and night daily injection of Lagenaria siceraria (100 mg/ 100 g b.w) for 30 days. After scarifying the mice, ileum samples were taken and passed the histological examination, also Histochemical stains were done. Results: From the cell biological, histochemical, and histopathological points of view, the carcinogen DMBA has a highly stimulatory effect on the cellular activities, DNA synthesis, RNA synthesis, and cell proliferative in the normal epithelial cells lining villi of the ileum of female mice, while Lagenaria siceraria has a highly inhibitory effect on the volume of the nuclei, DNA synthesist, and the cell proliferation of the DMBA-induced cells lining villi of the ileum of female mice. Conclusion: Finally, it could be said that the carcinogen DMBA has a proliferative and/or possibly a carcinogenic effect on the ileum of female mice. Also, It could be concluded that Lagenaria siceraria could be offered an antiproliferative and/or possibly an anti-carcinogenic effect against DMBA.

Effect of Sphagneticola Trilobata Extract on Histological Wistar Rat Kidney Induced by DMBA

One factor can trigger the growth and development of cancer cells is free radicals that are from carcinogenic compounds such as dimethylbenz (α) anthracene (DMBA). The use of plant extracts as a preventive or curative in cases of tumors/cancer has been reported, however there is no reports about the in vivo study for Sphagneticola trilobata plant. S. trilobata is an herbal plant that has pharmacological activities, potential to be developed as anticancer agent. This study aims to examine the anticancer effect of the methanol extract of S. trilobata leaves using histology observation on Wistar rat (Rattus novergicus) kidney which was induced by 7,12 dimethylbenz [α] anthracene (DMBA). The study used a completely randomized design with female rats (15 rats) grouped into 5 treatment groups, namely (i) the normal treatment group (KN), (ii) the DMBA-only treatment group (negative control, K(-)), (iii) the first dose (200 mg / kg BW) treatment group (KI), (iv) the second dose (300 mg / kg BW) treatment group (KII), and (v) the third dose (400 mg / kg BW) treatment group (KIII). DMBA was given orally at a concentration of 18 mg / kg BW for 4 times then continued for the extract. The results showed that cell damages (degeneration, necrosis and inflammation) were found mostly in negative controls. The dosage of 200 mg / kg BW of S. trilobata extract was the optimum dose in this study which was able to inhibit histological damage of kidney organs exposed to carcinogens DMBA by decreasing the level of degeneration, necrosis and inflammation.

Antiskin Cancer and Antioxidant Activities of Formulated Agar from Brown Seaweed Laminaria digitata (Hudson) in Dimethyl Benzanthracene-Induced Swiss Albino Mice

This study explores the antiskin cancer effect of formulated agar (FA) from Laminaria digitata on dimethyl benzanthracene- (DMBA-) induced skin cancer mice. The agar was extracted and formulated (emulgel), and FA was biochemically characterized. The in vitro cytotoxicity of FA was tested using NTT 3T3 mice fibroblast cells. The mice were divided into 5 groups: group 1 served as control mice, group 2 mice were considered as DMBA-induced cancer control, group 3 mice were FA pretreated (low dose) + DMBA-induced mice, group 4 mice were FA pretreated (high dose) + DMBA-induced mice, and group 5 were positive control + DMBA-induced mice. The behaviour and biochemical markers of cancer were significantly decreased in group 2 (DMBA-induced) mice, which were brought to near normalcy by FA pretreated mice (groups 3 and 4). The levels of p53 and keratin were significantly elevated in group 2 mice and these levels were decreased in 3 and 4 mice as well. The histopathological examination of DMBA-induced mice was shown degenerated cervical patches in the skin, cirrhosis in liver, oedema in the renal tissue, and swollen and damage in cardiac tissue, which were reduced for the mice applied with FA. This confirms that FA pretreatment offered potential antiskin cancer property.

Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is disrupted in the pathological development of cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. To investigate the impact of DLX3 expression on cSCC prognosis, we carried out clinicopathologic analysis of DLX3 expression which showed statistical correlation between tumors of higher pathologic grade and levels of DLX3 protein expression. Further, Kaplan-Meier survival curve analysis demonstrated that low DLX3 expression correlated with poor patient survival. To model the function of Dlx3 in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on mice genetically depleted of Dlx3 in skin epithelium (Dlx3cKO). Dlx3cKO mice developed significantly more tumors, with more rapid tumorigenesis compared to control mice. In Dlx3cKO mice treated only with DMBA, tumors developed after ~16 weeks suggesting that loss of Dlx3 has a tumor promoting effect. Whole transcriptome analysis of tumor and skin tissue from our mouse model revealed spontaneous activation of the EGFR-ERBB2 pathway in the absence of Dlx3. Together, our findings from human and mouse model system support a tumor suppressive function for DLX3 in skin and underscore the efficacy of therapeutic approaches that target EGFR-ERBB2 pathway.

Thymoquinone Increased Expression of CD4CD25Treg in Sprague-Dawley Rats Induced Dimethylbenzanthracene

BACKGROUND: The carcinogen dimethylbenzanthracene (DMBA) is immunotoxic. Thymoquinone, meanwhile, is known to have antioxidant and anti-inflammatory effects. AIM: This study aims to determine the effect of thymoquinone and tamoxifen on the CD4CD25Treg count in Sprague-Dawley (SD) rats induced by DMBA. METHODS: The 50 SD rats were divided into five groups. Group I (normal control) was given standard drinking and food. Group II was given thymoquinone, Group III was given tamoxifen, Group IV was given DMBA, and Group V was given solvent control. Thymoquinone, tamoxifen, and solvent control administration started 2 weeks before DMBA administration and continued during DMBA induction. In the 3rd week, except for the normal group, all groups were created to be induced with 10 × 20 mg/kg body weight of DMBA for 5 weeks. In the 21st week, surgery and data collection were performed. The hematology profile and CD4CD25Treg number were carried out employing a flow cytometer. The difference in the average number of CD4CD25Treg and blood cells between groups was analyzed with one-way analysis of variance RESULTS: The results revealed that DMBA induction reduced the number of erythrocytes, HB levels, platelet counts, and leukocyte counts (p < 0.05). The administration of thymoquinone and tamoxifen reduced the hematopoiesis effect of DMBA. The thymoquinone and tamoxifen group had a higher number of CD4CD25Treg and leukocytes than the DMBA group (p < 0.05). CONCLUSION: There was no difference in the average CD4CD25Treg, leukocyte count, lymphocyte count, and monocyte count between the thymoquinone and the tamoxifen groups (p > 0.05).

Curcumin Nanoparticle Enhances the Anticancer Effect of Cisplatin by Inhibiting PI3K/AKT and JAK/STAT3 Pathway in Rat Ovarian Carcinoma Induced by DMBA.

Cisplatin has been used for decades for the treatment of ovarian cancer. However, despite its potent anticancer effect, cisplatin’s efficacy as a single agent was inadequate in patients with advanced stage. Curcumin has been shown to sensitize cisplatin activity in several cancer models. However, the low bioavailability of curcumin has limited its anticancer potential. Hence, nano-formulation of curcumin was developed to increase its therapeutic efficacy in ovarian cancer. The objective of this study was to investigate the mechanism of curcumin nanoparticles given in combination with cisplatin in rat ovarian carcinoma induced by dimethylbenz(a)anthracene (DMBA). The administration of cisplatin and nanocurcumin resulted in a significant reduction in ovarian tumor volume and weight. Furthermore, there were reduction in expressions of Ki67, TGF-β, PI3K, and Akt phosphorylation. Co-treatment of cisplatin and nanocurcumin also reduced JAK expression, STAT3 phosphorylation, and reduced IL-6 concentrations. Altogether, nanocurcumin, given as a co-treatment with cisplatin has therapeutic potential in ovarian cancer models by inhibiting proliferation through downregulation of PI3K/Akt and JAK/STAT3 signaling pathways.

Retraction Note: Chemopreventive Potential of Resveratrol in Mouse Skin Tumors Through Regulation of Mitochondrial and PI3K/AKT Signaling Pathways.

To investigate the chemopreventive potential of resveratrol, a phytoalexin found in seeds and skin of grapes, berries and peanuts in 7,12 dimethyl benz(a)anthracene (DMBA) induced mouse skin tumorigenesis. Topical treatment of resveratrol was given to the animals 1 h prior to DMBA for 28 weeks. At the end of the study period, the skin tumors were dissected out and western blotting was carried out to examine the regulation of proteins involved in anti-tumorigenesis in response to resveratrol. Chemopreventive properties of resveratrol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Results of the western blotting showed that resveratrol treatment increased the DMBA suppressed p53 and Bax while decreased the expression of Bcl-2 and Survivin. Further, resveratrol supplementation resulted in release of cytochrome C, caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. Resveratrol was also found to inhibit skin tumorigenesis through regulation of Phosphatidylinositol-3-kinase (PI3K)/ and AKT proteins which are implicated in cancer progression because it stimulates proliferation and suppresses apoptosis. Based on the results we can conclude that resveratrol regulates apoptosis and cell survival in mouse skin tumors as mechanism of chemoprevention hence deserve to be a chemopreventive agent.

The antimammary tumor effects of ethanolic extract of propolis from Adamawa region (Cameroon) are by apoptosis via reactive oxygen species-mediated mitochondrial pathway.

Identification of novel natural treatment to combat cancer is a current need. This study was aimed at assessing the anticancer effects of ethanol-extracted Cameroonian propolis (EEP). The antitumor effect of EPP was evaluated in vitro by measuring; cell viability, cell cycle, cell death mechanism, cell migration/invasion, reactive oxygen species (ROS), mitochondrial potential (ΔΨm), caspase activity, and apoptosis-regulating proteins (Bcl-2 and Bcl-XL) in cell lines. In vivo, the effect of EEP against 7,12 dimethylbenz(a)anthracene (DMBA)-induced breast tumorigenesis in rats was assessed. EEP was found to induce cytotoxicity against ER negative MDA-MB-231 breast cancer cells by activating apoptosis through ROS-mediated mitochondrial pathway. The extract equally triggered caspase-3 and caspase-9, increment of ROS level, disruption of ΔΨm and down-regulation of Bcl-XL and Bcl-2 proteins. Besides, EPP prevented migration and invasion activities by inhibiting MMP-2 activity. At all doses it prevented breast tumor incidence (20% in EEP 150 mg/kg vs 70% in DMBA) as well as tumor burden. Tumor sections from EEP-treated rats showed middle proliferation of mammary ducts with weak inflammatory responses. In summary, Cameroonian propolis exhibited antimammary tumor effects via the intrinsic pathway of apoptosis.

Chemopreventive effect of Quercus infectoria galls on DMBA induced mouse skin tumorigenesis

Chemoprevention is an important strategy to control the process of carcinogenesis and a number of plants with anti-cancer properties are being researched, some of which have shown promising results. Quercus infectoria galls is a well-known medicinal plant which has been used in medicine as larvicidal, anti-inflammatory, antibacterial, anti-fungal, antioxidant, and antidiabetic properties. The present study was carried out to evaluate the anti-tumor activity of the aqueous extract on the two stage process of skin carcinogenesis, consisting of initiation with a single topical application of a carcinogen 7, 12 - dimethylbenz (a) anthracene (DMBA) followed by a promoter (croton oil) three times in a week were employed. A significant reduction in tumor incidence, tumor burden, tumor yield, and cumulative number of papilloma was observed, along with a significant increase in average latent period in mice treated orally with 2 gm/kg of Quercus infectoria galls extract as compared to the positive control group treated with DMBA plus croton oil administered. Furthermore, Histopathological alterations in the carcinogen-treated control animals were also observed in the form of epidermal hyperplasia, keratinized pearl formation, and acanthosis in skin and tumors, whereas these were found to be reduced significantly before and after galls extract oral administration. The results thus concluded that Quercus infectoria galls extract exhibits significant anti-tumor activity and may serve in future drug development programs for the cancer prevention of skin cancer.

Suppression of hypoxia and inflammatory pathways by Phyllanthus niruri extract inhibits angiogenesis in DMBA-induced breast cancer mice.

Background and purpose:Angiogenesis has been one of the hallmarks of cancer. In recent years, Phyllanthus niruri extract (PNE) was reported to inhibit angiogenesis by decreasing the levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in breast cancer. However, the experimental results were confirmed in cancer cell lines only, whereas the anti-angiogenic activity in animal models has not been demonstrated. In this study, we tried to examine the anti-angiogenic activity of PNE on BALB/c strain mice models that were induced for breast cancer using the carcinogenic substance 7,12- dimethylbenz[a]anthracene (DMBA).Experimental approach:Experimental animals were divided into five different groups; vehicle, DMBA, PNE 500 mg/kg, PNE 1000 mg/kg; and PNE 2000 mg/kg. Mammary carcinogenesis was induced using a subcutaneous injection of 15 mg/kg of DMBA for 12 weeks. Afterward, oral PNE treatment was given for the following 5 weeks. VEGFA and HIF-1α were observed using immunohistochemistry. Endothelial cell markers CD31, CD146, and CD34 were observed using the fluorescent immunohistochemistry method. The levels of interleukin-6 (IL-6), IL-17, and C-X-C motif chemokine (CXCL12) were measured using flow cytometry.Findings/Results:The survival analysis indicated that PNE increased the survival rate of mice (P = 0.043, log-rank test) at all doses. The PNE treatment decreased the immunoreactive score of angiogenic factors (VEGF and HIF-1α), as well as the endothelial cell markers (CD31, CD146, and CD34). The PNE- treated groups also decreased the levels of inflammatory cytokines (IL-6, IL-17, and CXCL12) at all doses.Conclusion and implications:This finding suggests that PNE may inhibit the progression of angiogenesis in breast cancer mice by targeting the hypoxia and inflammatory pathways.

Oral cancer preventive potential of Polydatin: A nanoencapsulation approach

Over the period, several medicinal plants are recognized as attractive sources of anti-cancer molecules. About 35,000 plant organisms have been tested for possible anticancer activities by the National Cancer Center (NCI). Among them, reproducible anticancer behavior has been shown by around 3,000 plant organisms. Based on this information, we aimed to investigate the cancer preventive efficiency of Polydatin encapsulated PLGA nanoparticles (POL-PLGA-NPs) against 7,12 dimethylbenz (a) anthracene (DMBA) induced buccal pouch carcinogenesis by modulating the antioxidants process in male Syrian hamsters. Oral cancer was initiated on left side buccal pouches by applying DMBA (0.5%), (a known potent chemical carcinogen) on alternative days in a week (thrice a week) for a period of 14 weeks to provoke oral cancer. Sequences of oral squamous cell carcinoma are noted to be manifested exhibiting the formation of incidence, size, mass and development of tumor presented as preneoplastic and neoplastic lesions in hamsters oral buccal pouch tissues. At the same time, oral administration of POL-PLGA-NPs (30mg/kg.b.wt.) considerably increased glutathione peroxidase (GPx) and glutathione (GSH) levels in the buccal tissue thereby decreasing lipid peroxidation activity which resulted in neoplasms incidence in buccal tissue of DMBA painted animals. Thus, POL-PLGA-NPs activity seemed to be a potent cancer preventive agent.

Nod2 protects mice from inflammation and obesity-dependent liver cancer

Nod2 is a pattern recognition receptor that modulates host innate immune responses and protects from inflammation, steatosis, and obesity. Obesity and inflammation are risk factors for hepatocellular carcinoma, however, the role of Nod2 in obesity-dependent hepatic tumorigenesis is not known. Here we tested the hypothesis that Nod2 protects from high fat diet (HFD)-dependent hepatic cancer. We used an obesity-dependent hepatic tumor model. WT and Nod2−/− mice were treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD. Nod2−/− mice treated with DMBA and maintained on HFD gain significantly more weight and develop more liver tumors than similarly treated WT mice. Livers of Nod2−/− tumorigenic mice had increased expression of genes involved in cell proliferation, immune responses, and cholesterol biosynthesis, increased infiltration of neutrophils, inflammatory monocytes, and T cells, and increased activation of STAT3 and ERK during the later stages of tumorigenesis. Bioinformatic analyses of genes with differential expression predicted an increase in cancer, immune, and cholesterol biosynthesis pathways. In summary, we have identified a novel role for Nod2 and demonstrate that Nod2 protects from HFD-dependent liver malignancy and this protection is accompanied by decreased cell proliferation, inflammation, steroid biosynthesis, neutrophils and macrophages infiltration, and STAT3 and MAPK signaling in the liver.

Cytotoxic and cancer chemopreventive potentials of the Anthonotha macrophylla P. Beauv aqueous extract on 7,12-dimethylbenz[a]anthracene-induced breast cancer in rats

Breast cancer is one of the leading causes of cancer deaths in women worldwide. Many women rely on plants as alternatives to prevent/treat cancer. Anthonotha macrophylla (Ceasalpiniaceae) is one of this ethnomedicinal plant used to cure cancer in Cameroon. This study was therefore undertaken to bring scientific evidence to this claim. The in vitro cytotoxicity of A. macrophylla aqueous extract was evaluated using resazurin reduction assay in five tumors and two non-tumor cell lines. Moreover, the chemopreventive potential of A. macrophylla aqueous extract was evaluated on 7,12 dimethylbenz[a]anthracene (DMBA) induced breast cancer in rats. The research focused on the incidence, burden, volume and histological analysis of breast tumors. In vitro, A. macrophylla extract exhibited cytotoxic effect in all tested cell lines with a CC50 ~ 279 and 132 μg/mL in human (MCF-7 and MDA-MB-231) and rodent breast cancer cells, respectively after 24 h. In vivo, the untreated DMBA-rats presented 100% of tumor incidence, while no tumor was detected in normal rats. Interestingly, a seven-month oral administration of A. macrophylla extract at the doses of 75 and 150 mg/kg BW resulted in a significant decrease of tumor incidence (p < 0.01 and p < 0.05), burden (70.01% and 53.28%) and volume (p < 0.001 and p < 0.01) compared to DMBA rats. The presence of polyphenols in the aqueous extract of Anthonotha macrophylla, as well as its antiradical properties, may account for its antitumor effects. These results therefore support the traditional use of Anthonotha macrophylla against breast cancer.

Effect of rosmarinic acid as a chemopreventive modality on experimentally induced hamster buccal pouch carcinogenesis

Abstract: The aim of the present study was directed to investigate the effect of rosmarinic acid (RA) as a chemopreventive modality on experimentally induced hamster buccal pouch (HBP) carcinogenesis. Material and methods: Forty Syrian male hamsters five weeks old, weighing 80-120g, were divided into four groups of ten animals in each as follows, GI: Topical application of liquid paraffin alone (three times a week for 14 weeks), GII: Topical application of 7, 12 dimethyl benz[a]anthracene (DMBA) alone (0.5% in liquid paraffin, three times a week for 14 weeks), GIII: Topical application of DMBA (0.5% in liquid paraffin, three times a week for 14 weeks) + Oral administration of RA (100mg/kg b.w in 1ml distilled water by oral gavage, three times a week for 14 weeks on alternate days of DMBA application), GIV : Oral administration of RA alone (100mg/kg b.w in 1ml distilled water by oral gavage, three times a week for 14 weeks). Results: Gross observation and histopathological findings revealed a-GI: normal stratified squamous epithelium b- GII: well and moderately differentiated SCC c-: GIII: revealed considerably reversed tumor incidence d: GIV: normal similar to GI. Immunohistochemical results revealed, oral administration of RA to DMBA treated hamsters restored the normal expression of bcl-2 and Bax indicating that RA may have chemopreventive mechanism and/or pro-apoptotic effects. Conclusion: RA may act through various mechanisms, such as exerting anti-inflammatory, antioxidant effects as well as inhibiting cell proliferation, migration, and selectively inducing cancer cells apoptosis.

Restraint stress abates the antioxidant potential of melatonin on dimethyl benz (a) anthracene (DMBA) induced carcinogenesis.

Free radical involvement in initiation, promotion and progression of carcinogenesis, implicates that scavengers of free radicals may act as inhibitors in the carcinogenic process. Melatonin, an antioxidant was used in the present study to evaluate its effectiveness on skin carcinogenesis induced by DMBA both with and without chronic restraint stress (CRS). Fifty Swiss albino young male rats were divided into five groups of 10 rats each as controls, topical DMB alone, Pre CRS-DMBA, melatonin DMBA and Pre-CRS-DMBA-melatonin treated groups. After 18 weeks blood was collected along with liver and skin samples. These were used for antioxidant enzyme assay, DNA damage and fluorescent spectra analysis. Melatonin showed antioxidant potential in combatting DMBA induced skin carcinogenesis measured by free radical scavenging enzymes and in vivo antioxidant status, DNA damage. Sensitive detection of the DMBA induced micro biochemical changes was possible by fluorescent spectroscopy from the transformed ratio of fluorescent intensity (F1 530 nm/630 nm) otherwise found constant for normal tissues. By melatonin treatment this ratio was similar to control values. The decreased antioxidant biochemical parameters depicting oxidative stress were comparable to comet assay and fluorescent studies, endorsing the chemo-preventive efficacy of melatonin against skin carcinogenesis caused by DMBA. CRS pre-exposure diminished the chemo-preventive/antioxidant ability of melatonin and the results were same as DMBA alone treatment, showing stress affected both cancer development and chemoprevention. CRS decreased the antioxidant potential of melatonin. Hence, managing stress could be perceived in cancer chemoprevention. Further studies focusing on stress reduction are needed.

Abstract 129: Apoptosis &amp; anti-proliferative nature of Aescin on 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis via downregulating Notch signaling

Abstract Worldwide, oral squamous cell carcinoma (OSCC) is the sixth most common cancer &amp; ranked as second most common cancer in India. The most implicated etiologic factors in the development of oral cancer is the use of tobacco, alcohol &amp; also HPV infection. Aescin, a pentacyclic triterpenoid saponin mixtures derived from Aesculus hippocastanum L (horse chestnut) that has been used as traditional herbal medicine, exists the pharmacodynamic properties, anti- edematous, anti-inflammatory &amp; antitumor. The present study, Tumors were induced by applying 0.5% DMBA topically to hamster buccal pouch (HBP) thrice a week for 14 weeks &amp; Aescin was orally administered at a various dose of 40 mg/kg body weight on alternate days of DMBA painting. We observed, reduced the tumor incidence, diminished lipid peroxidation, &amp; elevation of antioxidants, liver marker enzymes by Aescin. Furthermore, aescin induced apoptosis in DMBA induced tumor bearing animals significantly inhibited cell to cell communication of Notch-1, Notch-2 &amp; its ligand &amp; Jagged-1 leads to inhibited expression of the Notch downstream signaling target Hes-1 &amp; Hey-1 analyzed by immunohistochemical analysis. These results clearly suggest that Aescin prevents lipid peroxidation, protects the antioxidant defense system, prohibit the dysplasia &amp; anti-carcinogenic potential. we concluded; the results provide an important new insight of Notch signaling pathway &amp; aescin might be developed as a potential chemo preventive agent for oral cancer. Key words: Oral cancer, aescin, antioxidant, apoptosis, chemopreventive, Notch signaling Citation Format: Hemavardhini Ramadoss, Suresh Kathiresan, Sanjay Gupta. Apoptosis &amp; anti-proliferative nature of Aescin on 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis via downregulating Notch signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 129.

HPV16 induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for HPV‐related penile cancer

Penile cancer is an under-studied disease that occurs more commonly in developing countries and 30-50% of cases show high-risk human papillomavirus (HPV) infection. Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV-related penile cancer. Ten-week-old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (Krt14) gene promoter and matched wild-type controls were exposed topically to dimethylbenz(a)anthracene (DMBA) or vehicle for 16 weeks. At 30 weeks of age, mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14, and of the HPV16 oncogenes E6 and E7 was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16-transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes E6 and E7 and showed deregulated cell proliferation, demonstrated by Ki67-positive supra-basal cells. HPV16-transgenic mice exposed to DMBA showed increased PeIN incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV-associated human penile cancers. Wild-type mice showed no malignant or pre-malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV-related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique in vivo tool for studying its biology and advancing basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Peroxiredoxin I deficiency increases keratinocyte apoptosis in a skin tumor model via the ROS-p38 MAPK pathway

Keratinocyte hyperproliferation is an essential link in skin cancer pathogenesis. Peroxiredoxin I (Prx I) is known to regulate cancer cell proliferation, differentiation, and apoptosis, but its role in skin cancer remains unclear. This study aimed to elucidate the role and mechanism of Prx I in skin cancer pathogenesis. Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were used to create a skin tumor model of the initiation/promotion stage of cancer. The role of Prx I in H2O2-induced keratinocyte apoptosis was also investigated. After DMBA/TPA treatment, Prx I deficiency was significantly associated with less skin tumors, lower Bcl-2 expression, and higher p-p38 and cleaved caspase-3 expressions in Prx I knockout tumors than in wild-type controls. H2O2 stimulation caused more cellular apoptosis in Prx I knockdown HaCaT cells than in normal HaCaT cells. The signaling study revealed that Bcl-2, p-p38, and cleaved caspase-3 expressions were consistent with the results in the tumors. In conclusion, the deletion of Prx I triggered the DMBA/TPA-induced skin tumor formation in vivo and in vitro by regulating the reactive oxygen species (ROS)-p38 mitogen-activated protein kinase (MAPK) pathway. These findings provide a theoretical basis for treating skin cancer.

Myrtenal averts apoptotic evasion of cancer cells in 7,12-dimethylbenz(a)anthracene induced experimental oral carcinogenesis

Apoptotic avoidance is one of the foremost characteristic features of tumour cells. Apoptotic induction in cancer cells could thus help to identify new anticancer agents from the natural products. The present study has taken an effort to investigate the apoptotic efficacy of myrtenal, a monoterpene, in 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinoma in male golden Syrian hamsters. The present study used the potent carcinogen, 7,12- dimethylbenz(a)anthracene, to develop oral tumours in the buccal pouches of the golden Syrian hamsters. Topical application of the above said carcinogen on the buccal mucosa (3 times a week for 14 weeks) resulted in well differentiated oral squamous cell carcinoma. The apoptotic potential of myrtenal was investigated using a spectrum of apoptotic markers, including pro-apoptotic and anti-apoptotic markers. Oral tumours developed in the buccal mucosa of hamsters showed higher expression of mutant p53 protein, Bcl-2 and lowered expression of Bax, Bad, Bid, caspase 3 and caspase 9. Myrtenal treatment at a dose of 230mg/kg bw orally to the hamsters treated with DMBA modulated the above said apoptotic markers towards tumour suppression or inhibition. The present findings thus suggests that the tumour preventive effect of myrtenal could partly be ascribed to its apoptotic induction potential during DMBA induced oral carcinogenesis.