Oral intake of bucillamine, carvedilol, metformin, or phenformin does not protect against UVR-induced squamous cell carcinomas in hairless mice.

Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice.

Possible treatment for UVB-induced skin injury: Anti-inflammatory and cytoprotective role of metformin in UVB-irradiated keratinocytes.

BACKGROUND: Excessive inflammation and cell death induced by ultraviolet (UV) cause skin photodamage. Metformin possesses anti-inflammatory and cytoprotective effects. However, whether metformin inhibits inflammation and cell death in UVB-induced acute skin damage is unclear. OBJECTIVE: To evaluate the anti-inflammatory and cytoprotective effects of metformin in vitro and in vivo. Furthermore, its potential mechanism has been explored. METHODS: Transcriptome sequencing and multiplex cytokines analysis were used to evaluate the validity of in vitro UVB-induced acute damage keratinocyte model and anti-inflammatory effects of metformin. We also determined the expression and nuclear translocation of CCAAT/enhancer-binding protein beta (C/EBPß), an important transcriptional factor of Interleukin-1beta (IL-1ß). Cell viability and cell death of keratinocytes were evaluated upon UVB irradiation in the presence or absence of metformin. 0.6% metformin cream was applied on UVB-irradiated mice to explore its pharmacological effects in vivo. RESULTS: Transcriptional landscape of 50 mJ/cm2 UVB-irradiated HaCaT cells is typical of UVB-induced acute damage keratinocyte model in vitro. Metformin alleviated transcription and secretion of IL-1ß, Tumor Necrosis Factor-alpha, and Fibroblast Growth Factor 2, expression and nuclear translocation of C/EBPß in this model. Metformin also protected keratinocytes from cell death caused by UVB-induced cellular secretions, which contributed to its cytoprotective effects. Topical administration of 0.6% metformin cream alleviated UVB-induced skin damage in mice. CONCLUSION: We proved the protective roles of metformin in UVB-challenged keratinocytes and UVB-irradiated mice, which indicated the potential value of metformin in topical therapy against skin photodamage.

Anti-Melanogenic Effects of Korean Red Ginseng Oil in an Ultraviolet B-Induced Hairless Mouse Model.

A 'remedy for all' natural product widely known in the Korean Peninsula is called Panax Ginseng Meyer. Globalization represents a persistent risk to the ozone layer, leading to bountiful amounts of Ultra-Violet B beams (UVB). The variety in human skin hues is ascribed to the characteristic color called Melanin. However, Melanin overproduction due to UVB beams promotes skin staining and tumorigenesis, a process called photo aging, which damages skin quality. To assess the effects of Korean Red Ginseng Oil (KGO) on photo aging, the murine melanoma cell lines B16/F10 were used in vitro and HRM-2 hairless mice exposed to UVB were studied in vivo. Our results revealed that KGO reduced tyrosinase activity and melanin production in B16/F10 cells along with the suppression of upstream factors involved in the melanin production pathway, both transcriptionally and transitionally. In the in vivo studies, KGO suppressed the expression of Matrix Metalloproteinase (MMP) and Interleukins along with a reduction of depth in wrinkle formation and reduced collagen degradation. Moreover, the feed intake and feed efficiency ratio that decreased as a result of UVB exposure was also improved by KGO treatment. In light of our results, we conclude that KGO can have considerable benefits due to its various properties of natural skin enhancement.

The effects of UVB irradiance on vitiligo phototherapy and UVB-induced photocarcinogenesis.

Phototherapy is the most commonly used modality for repigmenting vitiligo. Currently, UVB emitting devices, including narrow-band UVB (NBUVB) and excimer laser/light, are considered as the treatment of choice. While emitting wavelengths at close proximity, excimer lights emit higher irradiance (HI; W/m2 ) compared to NBUVB. Clinical reports have shown that excimer light is more efficacious in treating vitiligo compared to NBUVB, and we demonstrated that irradiance plays a critical role in promoting melanoblasts differentiation. UVB radiation from the sun is closely associated with photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance (low irradiance (LI) UVB). Sunscreen use was associated with skin cancer reduction in clinical trials. Paradoxically, sunscreen use was associated with increased sunburn episodes in the real-world settings. It was shown that UVB-induced sunburn depends on fluence (J/m2 ) but not irradiance of UVB radiation. We investigated the significance of irradiance in the context of UVB-induced carcinogenesis of the skin. For mice receiving equivalent fluence of UVB exposure, the LIUVB-treated mice showed earlier tumor development, larger tumor burden, and more epidermal keratinocytes harboring mutant p53 as compared to their HIUVB-treated counterparts. These results suggested that at equivalent fluence, LIUVB radiation has more photocarcinogenic potential on the skin compared to its HI counterpart. Since development of sunburn with or without sunscreen use indicates that certain threshold of UVB fluence has been received by the skin at LI and HI, respectively, sunburn episodes with sunscreen use (LIUVB) are more damaging to the skin compared to that without sunscreen (HIUVB) application. In summary, since irradiance plays an important role determining the biological effects of UVB radiation on the skin, future related studies should take this critical parameter into consideration.

Distinguishing Myth from Fact: Photocarcinogenesis and Phototherapy.

Ultraviolet (UV) radiation contributes to the development of skin cancer through direct and indirect DNA damage, production of reactive oxygen species, and local immunomodulation. The association between UV radiation and skin cancer has raised concern for the risk of carcinogenesis following phototherapy. The photocarcinogenic impact of psoralen and UVA radiation (PUVA) has been extensively studied, whereas limited safety studies exist for other phototherapy modalities, such as broadband and narrowband UVB and UVA1. Because of the as of yet unclear risk, patients who have undergone any type of phototherapy should be followed for age-appropriate skin cancer screening.

A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients.

AIMS: Vitamin C plays a role in chemoprevention in cancer treatment, and Vitamin C modulates many regulators of inflammation in in vitro studies. The aim of this study is to assess the effect of Vitamin C supplementation with neoadjuvant chemoradiation in esophageal adenocarcinoma on the nuclear factor-kappa B (NF-κB) and associated cytokines. MATERIALS AND METHODS: A total of 20 patients undergoing multimodal treatment for esophageal adenocarcinoma were randomized to receive Vitamin C (1000 mg/day) orally for 4 weeks or no supplementation. Pre- and post-Vitamin C endoscopic biopsies were used for the study of NF-κB activity and cytokine analysis. RESULTS: NF-κB activity along with cytokines was activated in the cancer tissue pretreatment. Down-regulation in NF-κB activity was observed in 25% of cases, two from the Vitamin C arm posttreatment. There was a significant reduction in cytokines levels in the cancer group, and this effect was more pronounced in the Vitamin C group (P < 0.05). CONCLUSIONS: Vitamin C supplementation had a mild protective effect in modulating of regulators of inflammation and carcinogenesis. Further studies with larger numbers of endpoints are needed to evaluate its effect on modulation of chemoradiation responses.

MECHANISTIC MODELING PREDICTS NO SIGNIFICANT DOSE RATE EFFECT ON HEAVY-ION CARCINOGENESIS AT DOSE RATES RELEVANT FOR SPACE EXPLORATION.

Heavy ion-induced carcinogenesis is a challenge for human space exploration, and mechanistically-motivated mathematical models are needed to predict space-relevant low dose-rate risks, which are difficult to measure experimentally, based on data at higher dose rates. We present such a model, which quantifies targeted and non-targeted radiation effects. We fitted it to lung carcinogenesis data in radon-exposed miners and rats, which provide valuable information on carcinogenesis from protracted exposure to densely-ionizing radiation. We generated model-based estimates for the dose-rate-effect, relative to acute exposures, on heavy ion-induced carcinogenesis at doses/dose rates expected during a Mars mission. A small and not statistically-significant dose-rate effect was predicted: 1.00 (95% CI: 0.54, 1.40) for human data and for combined human and rat data 0.93 (0.06, 1.49). Consequently, heavy ion carcinogenesis estimates from moderate/high dose-rate experimental data may be applicable to doses/dose rates relevant for space exploration.

Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D3.

Three decades ago, the Garlands postulated that vitamin D3 produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D3 has anticancer effects, thus triggering more than 9,500 publications on D3 and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D3 influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D3 in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D3-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D3 may not mimic all possible beneficial effects of UVR, and uncovering non-D3-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. Cancer Prev Res; 11(7); 383-92. ©2018 AACR.

Juglanin ameliorates UVB­induced skin carcinogenesis via anti­inflammatory and proapoptotic effects in vivo and in vitro.

Ultraviolet (UV) radiation induces skin injury, and is associated with the development and formation of melanoma, which is a highly lethal form of skin cancer. Juglanin is a natural product, which is predominantly extracted from Polygonum aviculare, and is considered a functional component among its various compounds. Juglanin has been reported to exert marked protective effects in various diseases via the inhibition of inflammation and tumor cell growth. The present study aimed to explore the effects of juglanin on human skin cancer induced by UV and to reveal the underlying molecular mechanism. In the present study, immunohistochemical analysis, western blot analysis, RT-qPCR analysis and flow cytometry assays were mainly used in vivo and/or in vitro. The results indicated that in mice, UVB exposure increased susceptibility to carcinogens, and accelerated disease pathogenesis. Conversely, juglanin was able to ameliorate this condition via inhibition of inflammation, suppression of cell proliferation and induction of apoptosis via p38/c­Jun N­terminal kinase (JNK) blockage, nuclear factor (NF)­κB inactivation and caspase stimulation in vivo. In addition, in vitro, the present study demonstrated that treatment of UVB­stimulated B16F10 melanoma cells with juglanin resulted in a dose­dependent decrease in cell viability, as well as increased apoptosis via the upregulation of caspase expression and poly (ADP­ribose) polymerase cleavage. In addition, juglanin markedly attenuated p38/JNK signaling, inactivated the phosphoinositide 3­kinase/protein kinase B pathway and suppressed UVB­induced NF­κB activation. Taken together, these results indicated the possibility of applying juglanin in combination with UVB as a potential therapeutic strategy for preventing skin cancer.

Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice.

An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-κB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.

[Chemoprevention of photocarcinogenesis using antioxidants].

The skin is constantly exposed to reactive oxygen species (ROS) from both endogenous and exogenous sources. Ultraviolet irradiation is a well-known contributor of photocarcinogenesis and photoaging, as it - among other things - promotes the production of ROS which damage nucleic acids, proteins and lipids. Topical or oral administration of antioxidants is presumed to counteract the damaging effects of ROS to the skin, thus potentially lowering the risk of skin cancers and skin aging. We review the current literature on chemoprevention of photocarcinogenesis using antioxidants.

The inhibitory effect of meadowsweet (Filipendula ulmaria) on radiation-induced carcinogenesis in rats.

PURPOSE: To examine the ability of the meadowsweet preparation to inhibit carcinogenesis induced by ionizing radiation in female rats. MATERIALS AND METHODS: The chemical composition of meadowsweet (Filipendula ulmaria) raw material (ethanol and aqueous extracts of meadowsweet flowers) has been studied for the presence of flavonoids, tannins and catechins. Adult female LIO strain rats were subjected to a single whole body γ-irradiation at a dose of 4 Gy in animal experiments. One group of irradiated rats served as control while the other group, starting from the 10th day after irradiation and until the end of the experiment, was given meadowsweet as a decoction of the flowers instead of drinking water. The average daily intake of meadowsweet (dry raw material) was 1 g/kg body weight. Rats were observed for 16 months. RESULTS: The analyzed meadowsweet extracts showed a sufficiently high content of flavonoids and tannins. In irradiated rats after 16 months the overall incidence of tumors was 79.6% (in 82 of 103 rats), the incidence of malignant tumors was 43.7% and the overall tumor multiplicity was 1.48. Most tumors were localized in the mammary gland - 57.3%. In rats that received meadowsweet, the incidence of all malignant tumors and overall multiplicity of tumors were significantly decreased by 1.5 and 1.3 times, respectively. The greatest reduction of many parameters has been identified for breast tumors: the overall incidence was decreased by 1.5 (p = 0.0174) and the overall multiplicity and multiplicity of malignant tumors - by 1.6 (p = 0.0002) and 2.2 (p = 0.0383) times, respectively. CONCLUSIONS: Meadowsweet preparation showed inhibiting activity on radiation carcinogenesis.

Anticarcinogenic activity of alpha-difluoromethylornithine, ginseng, eleutherococcus, and leuzea on radiation-induced carcinogenesis in female rats.

PURPOSE: To carry out a comparative study of inhibition of radiation carcinogenesis using alpha-difluoromethylornithine (DFMO), tinctures of ginseng, eleutherococcus and leuzea in female rats. MATERIALS AND METHODS: Locally bred female LIO-strain rats were subjected to a single whole body γ-irradiation dose of 4 Gy at 12 weeks of age. Modifying drugs were given with drinking water from the 10th day after irradiation until the end of the experiment (for 16 months). RESULTS: Irradiated rats developed tumors 70.0-79.6% (malignant tumors: 43.7-45.0%) with a multiplicity of 1.48-1.75 (malignant: 0.5-0.58), while in unirradiated animals the incidence of all/malignant tumors was 21.9%/7.7% with multiplicity of 0.22/0.08. In exposed rats tumors most often developed in the mammary gland - 57.3%, reproductive and endocrine organs - 27.2%, and other localizations - 29.1%. All drugs, except leuzea, significantly reduced incidence and multiplicity of tumors, overall or at some localizations in irradiated rats. Highest, and practically equal inhibition, was shown by ginseng and DFMO, while eleutherococcus was clearly inferior. Ginseng reduced overall tumor incidence and multiplicity by 1.5 and 2.4 times, malignant tumor incidence and multiplicity - by 2.5 and 2.9 times, respectively. CONCLUSIONS: The ginseng extract is the most promising radiation carcinogenesis inhibitor tested.

[Phototherapy and carcinogenesis]. / Phototherapie und karzinogenese.

Phototherapy successfully uses the short-term effects of ultraviolet light against inflammation and proliferation. For its long-term effects, however, ultraviolet light was recently classified as a carcinogen. The wave spectrum employed in phototherapy has various carcinogenic effects in experimental systems, most notably DNA mutations in keratinocytes. Clinically, PUVA increases the risk for squamous cell carcinoma of the skin, especially after following 350 or more phototherapy sessions over a lifetime. Melanoma and genital skin cancer are not increased by PUVA alone. Previous UV damage, immunosuppression and other systemic treatments increase cutaneous carcinogenesis through PUVA. In contrast, broad-band UVB, narrow-band UVB and UVA1 have not yet been linked to cutaneous carcinogenesis, but will need careful follow-up in larger studies. Phototherapy remains a safe treatment modality, provided that the indication is well-founded, previous exposure and co-carcinogens are considered, and short and dose-intensive treatment protocols are favored, PUVA is chosen as second-line treatment that should not be used for more than a lifetime total of 250-300 phototherapy sessions.

Cancer risks related to low-level RF/MW exposures, including cell phones.

For years, radiofrequency (RF) and microwave (MW) radiations have been applied in the modern world. The rapidly increasing use of cellular phones called recent attention to the possible health risks of RF/MW exposures. In 2011, a group of international experts organized by IARC (International Agency for Research on Cancer in Lyon) concluded that RF/MW radiations should be listed as a possible carcinogen (group 2B) for humans. Three meta-analyses of case-control studies have concluded that using cell phones for more than ten years was associated with an increase in the overall risk of developing a brain tumor. The Interphone Study, the largest health-related case-control international study of use of cell phones and head and neck tumors, showed no statistically significant increases in brain cancers related to higher amounts of cell phone use, but excess risk in a small subgroup of more heavily exposed users associated with latency and laterality was reported. So far, the published studies do not show that mobile phones could for sure increase the risk of cancer. This conclusion is based on the lack of a solid biological mechanism, and the fact that brain cancer rates are not going up significantly. However, all of the studies so far have weaknesses, which make it impossible to entirely rule out a risk. Mobile phones are still a new technology and there is little evidence about effects of long-term use. For this reason, bioelectromagnetic experts advise application of a precautionary resources. It suggests that if people want to use a cell phone, they can choose to minimize their exposure by keeping calls short and preferably using hand-held sets. It also advises discouraging children from making non essential calls as well as also keeping their calls short.

Lipoteichoic acid from Lactobacillus rhamnosus GG as an oral photoprotective agent against UV-induced carcinogenesis.

Probiotics are live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Cell surface molecules of these micro-organisms are being studied in relation to their ability to interact with the host. The cell wall of lactobacilli possesses lipoteichoic acids (LTA) which are molecules with immunomodulatory properties. UV radiation (UVR) has been proposed as the main cause of skin cancer because of its mutagenic and immunosuppressive effects. Photoprotection with some nutrition interventions including probiotics has recently been shown. The aim of the present study was to investigate whether the oral administration of purified LTA from Lactobacillus rhamnosus GG can modulate the immune-suppressive effect of UVR and skin tumour development in female Crl:SKH-1-hrBR mice. For this purpose, two irradiation models were studied: (1) a chronic irradiation scheme consisting of daily irradiations during twenty consecutive days and (2) a long-term irradiation schedule, irradiating the animals three times per week, during 34 weeks for tumour development. The results showed that T-cells in the inguinal lymph node of LTA-treated mice produced higher levels of (1) interferon-γ and (2) a number of total, helper and cytotoxic T-cells compared with non-treated mice. Moreover, a significant delay in tumour appearance was found in LTA-treated mice. An increased IgA⁺ cell number was found in the small intestine together with a higher number of activated dendritic cells in the mesenteric lymph nodes. The latter results might be indicative of a direct effect of LTA in the gut, affecting the cutaneous immune system and restoring homeostasis through the gut-skin axis.