Mouse Skin Tumorigenesis Research Articles

Loss of CELF2 promotes skin tumorigenesis and increases drug resistance.

CELF2 belongs to the CELF RNA-binding protein family and exhibits antitumor activity in various tumor models. Analysis of the pan-cancer TCGA database reveals that CELF2 expression strongly correlates with favorable prognosis among cancer patients. The function of CELF2 in nonmelanoma skin cancer has not been studied. We used shRNA-mediated knockdown (KD) of CELF2 expression in human squamous cell carcinoma (SCC) cells to investigate how CELF2 impacted SCC cell proliferation, survival, and xenograft tumor growth. We determined CELF2 expression in human SCC tissues and adjacent normal skin using immunofluorescence staining. Additionally, we investigated the changes in CELF2 and its target gene expression during UV-induced and chemical-induced skin tumorigenesis by western blotting. CELF2 KD significantly increased SCC cell proliferation, colony growth, and SCC xenograft tumor growth in immunodeficient mice. CELF2 KD in SCC cells led to activation of KRT80 and GDF15, which can potentially promote cell proliferation and tumor growth. While control SCC cells were sensitive to anticancer drugs such as doxorubicin, SCC cells with CELF2 KD became resistant to drug-induced tumor growth retardation. Finally, we found CELF2 expression diminished during both UV- and chemical-induced skin tumorigenesis in mice, consistent with reduced CELF2 expression in human SCC tumors compared to adjacent normal skin. This study shows for the first time that CELF2 loss occurs during skin tumorigenesis and increases drug resistance in SCC cells, highlighting the possibility of targeting CELF2-regulated pathways in skin cancer prevention and therapies.

Retraction Note: Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis.

Retraction Note: Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis.

SIRT6 pharmacological inhibition delays skin cancer progression in the squamous cell carcinoma

Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacological modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the pro-differentiating effects of SIRT6 silencing, as the levels of Keratin 1, Keratin 10 and Loricrin were upregulated compared to controls. Next, the effects of SIRT6 pharmacological modulation were evaluated in a DMBA-TPA-induced skin cancer mouse model. Mice treated with the inhibitor S6 in a preventive approach, i.e. at the beginning of the promotion stage, presented reduced number and size of papillomas, compared to the controls. The epidermal hyperproliferation marker Keratin 6 and the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed compared to untreated lesions. In a therapeutic approach, i.e. treatment starting after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated mice displayed an opposite trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, with a higher E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results confirm that SIRT6 plays a role in skin carcinogenesis and suggest SIRT6 pharmacological inhibition as a promising strategy in cSCC.

Antioxidant and Antitumorigenic Activities of the Standardized Water Extract From Fruit of Terminalia chebula Retz. var. chebula

Background Terminalia chebula Retz. var. chebula ( T chebula) has been traditionally used as a crude drug for treating various diseases, including skin disorders. This study aimed to investigate the potential antioxidant effects and antitumorigenic activity of an aqueous extract from the fruit of T chebula. Methods The extract's total phenolic content and antioxidant activity were measured using Folin-Ciocalteu, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) tests, respectively. The 2 ´,7 ´-dichlorodihydrofluorescin diacetate assay was employed to evaluate the extract's ability to reduce intracellular reactive oxygen species (ROS) in U-937 human monocytic cell lines which had been treated with hydrogen peroxide for 30 min. Male ICR mice ( n = 30, 5 groups) were used to investigate the influence of T chebula extract on dimethylbenz[a]anthracene (DMBA)/12- O-tetradecanoylphorbol 13-acetate (TPA)-induced carcinogenesis. After 20 weeks of treatment with T chebula extract, tumor incidence, size, and number were assessed. The major phenolic compounds in the extract were determined using high-performance liquid chromatography. Statistical analysis was performed using ANOVA followed by post hoc least significant difference test. Results T chebula extract effectively reduced intracellular ROS and scavenged antioxidants in vitro. The IC50 values of the extract as measured by DPPH and FRAP assays were 109.0 ± 14.5 μg/mL and 2.39 ± 0.17 μg/mL, respectively. Moreover, 4 mg of T chebula extract significantly decreased the incidence, volume, and number of tumors in DMBA/TPA-induced skin tumorigenesis in mice. Conclusion T chebula extract effectively reduced intracellular ROS, and significantly decreased the incidence, volume, and number of tumors in DMBA/TPA-induced skin tumorigenesis in mice. These findings suggest that T chebula extract could be a promising therapeutic agent for skin tumors and other oxidative stress-related diseases.

Chemopreventive effects and anti-tumorigenic mechanisms of Actinidia arguta, known as sarunashi in Japan toward 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- induced lung tumorigenesis in a/J mouse

Previously, we reported the inhibitory effect of Actinidia arguta juice, known as sarunashi juice (sar-j) in Japan, on mutagenesis, inflammation, and mouse skin tumorigenesis. The components of A. arguta responsible for the anti-mutagenic effects were identified to be water-soluble, heat-labile phenolic compounds. We proposed isoquercetin (isoQ) as a candidate anticarcinogenic component. In this study, we sought to investigate the chemopreventive effects of A. arguta juice and isoQ on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, and identify the possible mechanisms underlying the anti-tumorigenic effects of A. arguta. The number of tumor nodules per mouse lung in the group injected with NNK and administered A. arguta juice orally was significantly lower than that in the group injected with NNK only. Oral administration of isoQ also reduced the number of nodules in the mouse lungs. As expected, the mutagenicity of NNK and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) detected using S. typhimurium TA1535 decreased in the presence of sar-j. However, NNK and MNNG mutagenicity detected using S. typhimurium YG7108, a strain lacking the O6-methylguanine DNA methyltransferases (ogtST and adaST) did not decrease in the presence of sar-j suggesting that sar-j may mediate its antimutagenic effect by enhancing the DNA damage repair by ogtST and adaST. Phosphorylation of Akt, with or without epidermal growth factor stimulation, in A549 cells was significantly decreased following sar-j and isoQ treatment, indicating that components in sar-j including isoQ suppressed the PI3K/AKT signaling pathways. Sar-j and isoQ reduced NNK-induced lung tumorigenesis. Sar-j targets both the initiation and growth/progression steps during carcinogenesis, specifically via anti-mutagenesis, stimulation of alkyl DNA adduct repair, and suppression of Akt-mediated growth signaling. IsoQ might contribute in part to the biological effects of sar-j via suppression of Akt phosphorylation, but it may not be the main active ingredient.

Evaluation of In-vivo Anticancer Activity Choerospondias axillaris in Swiss Albino Mice Models

Background and Objective: The fruits of the plant, Choerospondias axillaris are one of the richest sources of flavonoids phenol and vitamin C that have been shown to possess a variety of biological activities. The present study was aimed to study the potential anti-cancer activity of the methanolic extract of fruit of Choerospondias axillaris using the in-vivo model to scientifically validate the folkloric use of the Choerospondias axillaris.
 Study Design: In-vivo model.
 Place and Duration of the Study: Department of pharmacology, Karnataka College of pharmacy, Bangalore India, between October 2021 to June 2022.
 Methods: Anti-cancer property of Choerospondias axillaris was evaluated against DMBA/croton oil induced skin tumorigenesis in Swiss albino mice. A single topical application of DMBA (100g/100l of acetone), followed 2 weeks later by repeated application of croton oil (1% in acetone three times a week) for 16 weeks. In contrast, animals treated orally with Choerospondias axillaris 200mg/kg/b.w. (group IV) and orally with Choerospondias axillaris 400mg/kg/b.w. (group V) and 5 Flu 10mg/kg (group III). The following parameters like; body weight, tumor incidence, cumulative number of tumors, tumor yield, average latency period, number of papillomas, haematological parameters, Serum Zinc and C-Reactive Protein, anti-oxidants enzyme, pro-inflammatory cytokines & Histopathological of Tumor skin studies were observed.
 Results: 100 percent tumor incidence exhibited in group II (DMBA/croton oil) whereas the group IV (Choerospondias axillaris 200mg/kg) and group V (Choerospondias axillaris 400mg/kg) and group III (5 Flu 10mg/kg) exhibited 50, 33.7 and 42.5% tumor incidence, which significantly lesser when compared to than group II (Toxic control). The cumulative number of papillomas during the observation period of 16 weeks was significantly decreased in the Choerospondias axillaris treated groups IV, V and III (9, 4 and 6 no’s tumor respectively) in comparison to 18 cumulative numbers of papillomas in carcinogen control group. The average latent period significantly increased in the Toxic control group to 3.2, 4.3, 6.5 and 5.4 in group II, IV, V and III respectively. Tumor yield were significantly lesser (1.5, 0.66 and 1.0) as compared to DMBA/Croton oil treated control. Furthermore, the level of LPO was significantly increased whereas, the activity of CAT level were significantly decreased in skin tissue of DMBA/Croton oil treated animals compared Choerospondias axillaris treated animals. Similarly, NLR (< 3.0), ESR, Serum Zinc and CRP have got improved in treated with Choerospondias axillaris. Protein expression of TGF-beta, IFN-G, TNF-alpha and IL-6 have shown Improvement in markers indicating a reduction in inflammation and immune imbalance in treated with Choerospondias axillaris compared with DMBA/Croton oil where shown moderate immune suppression.
 Conclusion: Based on the results it can be concluded that the test drug Choerospondias axillaris could be a potential candidate for the treatment of skin cancer.

Interleukin-38 promotes skin tumorigenesis in an IL-1Rrp2-dependent manner.

Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin cancer.

Editorial Expression of Concern for: Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis.

Editorial Expression of Concern for: Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis.

Anti-inflammatory, Antinociceptive, and Antitumorigenesis Activities of Terminalia Bellerica (Gaertn.) Roxb. in Animal Models

Previous pharmacological research has demonstrated that Terminalia bellerica (Gaertn.) Roxb. (TB) extract possesses several pharmacological activities. However, there is scant evidence documenting the therapeutic activities of TB extract on inflammation, pain, and cancers. Our study examined the in vivo anti-inflammation, antinociception, and antitumorigenesis effects of TB extract and investigated possible mechanisms for those effects. Anti-inflammation activities of TB extract were evaluated using ethyl phenylpropiolate (EPP)- and arachidonic acid (AA)-induced ear edema models, a cotton pellet-induced granulation formation model, and a carrageenan-induced hind paw edema model. An antinociceptive property of TB extract was assessed using a formalin-induced nociception test. An anticarcinogenesis effect was investigated using a 7,12-dimethylbenz( a) anthracene (DMBA) and 12- O-tetradecanoylphorbol-13-acetate (TPA)-induced tumorigenesis model. In the study, TB extract exhibited significant anti-inflammatory effects against EPP-induced ear edema and carrageenan-induced hind paw edema in rats. However, the TB extract showed insignificant inhibitory activity against AA-induced ear edema and cotton pellet-induced granuloma. A dose-dependent decrease in analgesic activity was observed with TB extract evidenced by decreased licking time in formalin-induced pain in mice in both the early and late phases. TB extract also significantly inhibited DMBA/TPA-induced mouse skin tumorigenesis. In conclusion, TB extract possesses anti-inflammatory, analgesic, and anticarcinogenesis properties which act, at least in part, through inhibitory effects of inflammatory mediator production.

Interleukin-38 promotes skin tumorigenesis via regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment in an IL-1Rrp2-dependent manner.

Abstract As the newest member of the IL-1 family, interleukin-38 (IL-38) has strong associations with chronic inflammatory diseases. However, its roles in tumorigenesis and the underlying mechanism remain poorly understood. Here, we demonstrated that IL-38, which was highly expressed in skin, downregulated in human cutaneous squamous cell carcinomas (CSCC) and 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoyl phorbol-13-acetate (TPA) induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice (IL-38 cKO) dramatically promoted skin tumor formation and their malignant progression. Mechanistically, IL-38 is dispensable for epidermal mutagenesis. IL-38 keratinocyte-specific deletion reduced proliferative gene expression along with epidermal cell proliferation and hyperplasia. Additionally, keratinocyte-specific deletion of IL-38 was associated with reduced secretion of inflammatory cytokines leading to a decreased infiltration of myeloid cells into the local tumor microenvironment, these inflammation-driven tumorigenesis are essential for carcinogenesis process. Furthermore, we first demonstrated that IL-38 activated the c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signal transduction pathway to promote proliferation and migration of tumor cells and expression of cancer-related inflammatory cytokines in an IL-1 receptor (IL-1R)-related protein 2 (IL-1Rrp2)-dependent manner. Together, our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2 /JNK and establish a new defined factor IL-38/ IL-1Rrp2 as therapeutic targets in skin cancer.

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.

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.

3′-Hydroxypterostilbene Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Mouse Skin Carcinogenesis

BackgroundA natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3′-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear. PurposeThe aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism. Study Design and MethodsThis study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated. ResultsThe results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes. ConclusionThis is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.

Protective Effects of Dietary Grape on UVB-Mediated Cutaneous Damages and Skin Tumorigenesis in SKH-1 Mice.

Non-melanoma skin cancers (NMSCs) are the most diagnosed cancers in the US and occur more frequently in males. We previously demonstrated chemoprotective effects of dietary grape powder (GP) against UVB-mediated skin tumorigenesis in female SKH-1 mice. To expand on this, here, we determined the effects of GP in a short-term UVB exposure protocol (0 or 5% GP, followed by UVB every other day for 2 weeks) in male and female SKH-1 mice, as well as explored any sex-related differences in UVB carcinogenesis via male SKH-1 mice (0, 3, or 5% GP; UVB twice weekly for 28 weeks). In the short-term study, we found that GP protects against early-stage epithelial hyperplasia and mast cell infiltration in both sexes. In the long term, GP markedly reduced tumor counts and malignant conversion, along with significant decreases in mast cell infiltration, serum IgE and Eotaxin. We also found inhibition of P38 phosphorylation and reduced PCNA, Ki67 and BCL2 levels, suggesting that the anti-inflammatory effects of GP inhibits P38, acting as an upstream regulator to inhibit proliferation and reduce tumor cell survival. Together, GP appears to protect against UVB-mediated skin damage and carcinogenesis in SKH-1 mice and should be explored further as a supplement for NMSC prevention.

The Inflammasome Adaptor ASC Delays UV-Induced Skin Tumorigenesis in Beta HPV38 E6 and E7 Transgenic Mice

Non-melanoma skin cancer is the most common cancer in fair-skinned adults and comprises basal cell carcinoma and squamous cell carcinoma (SCC). Its incidence reaches 1 of 100 person-year in Australia (Lomas et al., 2012) and is still on the rise worldwide (Madan et al., 2010). The development of non-melanoma skin cancer depends on genetic and environmental factors. Particularly, there is clear evidence that cumulative sun exposure contributes to the development of non-melanoma skin cancer (Ananthaswamy et al., 1997; Madan et al., 2010).

Targeted delivery of thermoresponsive polymeric nanoparticle-encapsulated lycopene: in vitro anticancer activity and chemopreventive effect on murine skin inflammation and tumorigenesis.

Naturally occurring lycopene has been reported for its chemopreventive and chemotherapeutic efficiency in various cancers, but its exceptional lipophilicity, poor aqueous solubility, instability, and consequently poor bioavailability limit its usage as a chemopreventive and chemotherapeutic agent. The present study aimed to synthesize co-polymeric nanoparticle-encapsulated formulations of commercial lycopene (NLY) and extracted lycopene (NLX) and evaluate their in vitro anticancer activity and inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin inflammation and tumorigenesis in Swiss albino mice. To prepare the nanoparticle-encapsulated formulations of lycopene, thermosensitive PNIPAAM–PEG-based co-polymeric nanoparticles were synthesized and characterized by FTIR spectroscopy, NMR spectroscopy, DLS, and TEM. Nanolycopene, unlike free lycopene, could be readily dispersed in aqueous media. Nanolycopene demonstrated stronger antioxidant activity and comparable in vitro anticancer efficacy to free lycopene against the melanoma cell line B16. Furthermore, nanolycopene showed comparable reduction of TPA-induced skin edema, expression of COX-2, and oxidative stress response. Additionally, it showed significant inhibition of tumor promotion. It also altered Bax and Bcl2 expressions, which led to the induction of apoptosis. The results also supported that the extracted lycopene-encapsulated nanoparticles may be a good alternative to the expensive commercial lycopene for cancer treatment.

Modulation of cancer signalling pathway(s) in two -stage mouse skin tumorigenesis by annonacin

BackgroundAnnonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved.MethodsMice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin.ResultsWith comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis.ConclusionsCollectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.

Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice.

The present study revealed the effects of Lycopene enriched tomato extract (LycT) on chemically induced skin cancer in mice. Skin tumors were induced by topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) [500nmol/100ul of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7nmol/100ul of acetone, twice a week for eighteen weeks] and LycT (5mg/kg b.w.) was administered orally. Male Balb/c mice were divided into four groups (n=15 per group): control, DMBA/TPA, LycT and LycT+DMBA/TPA. The chemopreventive response of LycT to skin tumorigenesis was evident by inhibition in tumor incidence, number, size, burden and volume in LycT+DMBA/TPA group when compared to DMBA/TPA group. This was associated with inhibition of cell proliferation in LycT+DMBA/TPA group as observed by the decrease in epidermal morphometric parameters and mRNA and protein expression of proliferating cell nuclear antigen when compared to DMBA/TPA group (p≤0.05). LycT decreased (p≤0.05) the mRNA and protein expression of angiogenic genes (vascular endothelial growth factor, angiopoietin-2, basic fibroblast growth factor) in LycT+DMBA/TPA group, suggesting its anti-angiogenic effects. The increase (p≤0.05) in protein expression of connexin-32 and 43 in LycT+DMBA/TPA group suggests improved inter cellular communication when compared to DMBA/TPA group. Histochemical studies demonstrated that the components of extracellular matrix (fibrous proteins and mucopolysaccharides) were also modulated during skin carcinogenesis and its chemoprevention by LycT. The decrease in cell proliferation parameters and expression of angiogenesis associated genes, modulation of ECM components and increase in expression of connexins suggest that LycT improved multiple dysregulated processes during chemoprevention of skin cancer.

142 Keratinocyte p38α ablation reveals a context-dependent regulation of tumor initiation, tumor type specification, maintenance, and malignant progression in several models of mouse skin tumorigenesis

142 Keratinocyte p38α ablation reveals a context-dependent regulation of tumor initiation, tumor type specification, maintenance, and malignant progression in several models of mouse skin tumorigenesis

Preventive effect of D-carvone during DMBA induced mouse skin tumorigenesis by modulating xenobiotic metabolism and induction of apoptotic events

The structural integrity and excellent immune system of the skin makes it a protective covering, inspite of its exposure to hazardous compounds. In the present study, the chemopreventive efficacy of D-carvone was studied in 7, 12-dimethylbenz[a]anthracene (DMBA) induced skin carcinogenesis. DMBA (25 μg in 0.1 m L−1acetone) was used to induce skin cancer in Swiss albino mice. Animals were randomly divided into six groups of six animals in each. Different concentrations of D-carvone (10, 20, 30 mg/kg body weight) were used to assess its anticancer effect. Tumor incidence, tumor volume, tumor burden, histological examination and levels of phase I and phase II detoxification agents were analyzed in experimental animals. Further, expression of p53 and various apoptotic proteins including- Bcl-2, Bax was analyzed using immunohistochemistry and enzymatic expression of apoptotic proteins caspase-3 and caspase-9 was carried out by using ELISA. We observed 100% tumor incidence in DMBA-painted animals and our results showed that D-carvone at 20 mg dose significantly prevents skin carcinogenesis. Our results also showed decreased levels of phase I enzymes (Cyt P450 and-Cyt b5) with increased levels of phase II enzymes (GR, GST and GSH) and increased expression of Bax, caspase-3 and caspase-9 with decreased expression of mutated p53 and Bcl-2 in animals treated with DMBA and D-carvone at 20 mg dose. The results of the present study suggest that D-carvone can be used as a chemopreventive agent against skin cancer, as it induces apoptosis in cancer. However, further studies are warranted to check chemopreventive efficacy of D-carvone on cell proliferation, angiogenesis, and metastasis before going to human trial.