Skin Cancer Model Research Articles

Curcumin mediates polyamine metabolism and sensitizes gastrointestinal cancer cells to antitumor polyamine-targeted therapies.

Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of polyamine metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or polyamine analogue. These studies provide insight into the polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.

Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer

Although the anticancer properties of extra virgin olive oil (EVOO) extracts have been recognized, the role of single compounds in non-melanoma skin cancer is still unknown. The in vitro chemopreventive and anticancer action of EVOO extracts and oil-derived compounds in non-melanoma skin cancer models were evaluated on cutaneous squamous cell carcinoma cells and on immortalized human keratinocytes stimulated with epidermal growth factor. Preparation of EVOO extracts and isolation of single compounds was carried out by chromatographic methods. Antitumor activity was assessed by cell-based assays (cell viability, migration, clonogenicity, and spheroid formation) and apoptosis documented by internucleosomal DNA fragmentation. Finally, inhibition of key oncogenic signaling nodes involved in the progression from actinic keratosis to cutaneous squamous cell carcinoma was studied by western blot. EVOO extracts reduced non-melanoma skin cancer cell viability and migration, prevented colony and spheroid formation, and inhibited proliferation of atypical keratinocytes stimulated with epidermal growth factor. Such a pharmacological activity was promoted by oleocanthal and oleacein through the inhibition of Erk and Akt phosphorylation and the suppression of B-Raf expression, whereas tyrosol and hydroxytyrosol did not have effect. The current study provides in vitro evidence for new potential clinical applications of EVOO extracts and/or single oil-derived compounds in the prevention and treatment of non-melanoma skin cancers.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Abstract IA15: Normal and cancer stem cells in multistage carcinogenesis

Abstract Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. In particular, tumors induced in mice by exposure to chemicals that act as mutagens or tumor promoters replicate many of the biologic and genetic features of multistage cancer in human populations. Such models often have a high burden of point mutations and gene copy number changes similar to human tumors of the lung, colon, or skin that are associated with exposure to exogenous environmental agents. These are important features that contribute to tumor heterogeneity—a major cause of drug resistance and poor response to therapy in human cancer patients. The availability of mouse models of tumors with a high mutation burden also offers possibilities for development of immunotherapy approaches that are dependent on expression of novel tumor antigens resulting from carcinogen-induced mutations in tumor DNA. Initiation of chemical carcinogenesis in the mouse is frequently caused by point mutations in genes of the Ras family. The nature of the initiating Ras mutation depends on the carcinogen used, but a similar “mutation signature” is seen throughout the genome of the initiated cell. Tumor cells, however, continually acquire additional new genetic alterations, leading to the emergence of multiple, genetically distinct tumor subclones. By combining the 4-color lineage tracing Confetti mouse with a chemical carcinogenesis model of skin cancer, we have investigated clonal and evolutionary dynamics at every stage of chemical carcinogenesis, from the initiated cell to benign tumors, malignant carcinomas, and ultimately to distant metastases. These studies reveal distinct patterns of clonal evolution at different stages of progression. The growth of subclones within tumors is driven by a stem cell population marked by expression of the Lgr6 gene—a known marker of normal skin stem cells and mediator of Wnt signaling in the epidermis. The use of mouse models for identification of patterns of clonal heterogeneity, and the drivers of clonal growth from cancer stem cells, may offer new possibilities for prevention or treatment of squamous carcinomas. Citation Format: Allan Balmain. Normal and cancer stem cells in multistage carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA15.

Raman biophysical markers in skin cancer diagnosis.

Raman spectroscopy (RS) has demonstrated great potential for in vivo cancer screening; however, the biophysical changes that occur for specific diagnoses remain unclear. We recently developed an inverse biophysical skin cancer model to address this issue. Here, we presented the first demonstration of in vivo melanoma and nonmelanoma skin cancer (NMSC) detection based on this model. We fit the model to our previous clinical dataset and extracted the concentration of eight Raman active components in 100 lesions in 65 patients diagnosed with malignant melanoma (MM), dysplastic nevi (DN), basal cell carcinoma, squamous cell carcinoma, and actinic keratosis. We then used logistic regression and leave-one-lesion-out cross validation to determine the diagnostically relevant model components. Our results showed that the biophysical model captures the diagnostic power of the previously used statistical classification model while also providing the skin's biophysical composition. In addition, collagen and triolein were the most relevant biomarkers to represent the spectral variances between MM and DN, and between NMSC and normal tissue. Our work demonstrates the ability of RS to reveal the biophysical basis for accurate diagnosis of different skin cancers, which may eventually lead to a reduction in the number of unnecessary excisional skin biopsies performed.

Immuno-modulatory effect of bio-plasma against cancer and other dreadful disease

The application of plasma medicine technology has been actively explored over last several years. Recently, non-thermal plasma has demonstrated potential as a safe anticancer therapeutic approach that can kill various types of cancer targets [1-4]. There is the urgent need of new human health care’s technology against cancers based on immuno-modulations. Main target of our study is to enhance efficacy and selectivity of plasma on cancer cells and cancer microenvironment by inducing immune-modulations. Fundamental insights on the cold plasma interactions with the immune cells and cancer micro-environment can clarify the basic mechanisms of plasma induced immune-stimulation. Recent preliminary study suggests that plasma significantly modulated immune cells and can induce cancer cell death in co-culture condition [5-7]. In one of our recent studies, using a monocyte cell model, we show that cold plasma activates the differentiation of monocytes into a macrophage-like phenotype and can increase mitochondrial/lysosomal numbers, suggesting that plasma may stimulate macrophage differentiation or activation. In turn, the interaction of plasma-activated macrophage cells reduced pro-tumorigenic features such as epithelial-mesenchymal-transition (EMT) and the stem-like population of tumor cells. Furthermore, plasma targeted macrophage activity and consequently enhanced apoptosis via expression of the TNF-α/NOS+ M1-like phenotype. In another study we have evaluated role of plasma induced damage associated molecular patterns/ immunogenic cell death in immune activation and cancer treatment in skin and oral cancer models. We have also initiated a study on plasma induced immuno-modulations for treatment of atopic dermatitis skin disorder. Present research work mainly comprises plasma induced activation of immune cells; which find applications for curing various kinds of resistant tumors and other dreadful diseases. Our main objectives are (i) to clarify basic mechanism on plasma induced immuno-modulations (ii) to develop immunomodulation based strategy for the treatment of various dreadful diseases including cancers (iii) to initiate clinical trial based on pre-clinical study.

Arthrospira Platensis - Potential in Dermatology and Beyond.

The search for natural products with benefits for health in general and of potential for treating human disease has gained wider interest world-wide. Here, we analyse current data on the microalga Arthrospira platensis (AP), that has been used in nutrition since ancient times in Fare East and African communities, for medical purposes with a focus on dermatology. Extracts of AP have been investigated in vitro and in vivo. The alga is rich in proteins, lipopolysaccharides and gamma-linolenic acid. AP extracts, phycocyanin compounds and polysaccharide calcium spirulan (Ca-SP) have been evaluated in various models. It could be demonstrated, that AP has significant antioxidant activity, prevents viruses from entry into target cells and inhibits the colonisation of wounds by multi-resistant bacteria. Furthermore, anti-cancer activity was documented in models of oral cancer, melanoma, and UV-induced non-melanoma skin cancer.

Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors

High numbers of mast cells populate the stroma of many types of neoplasms, including human papilloma virus-induced benign and malignant tumors in man and mouse. Equipped with numerous pattern recognition receptors and capable of executing important pro-inflammatory responses, mast cells are considered innate sentinels that significantly impact tumor biology. Mast cells were reported topromote human papilloma virus (HPV)-induced epithelial hyperproliferation and neo-angiogenesis in an HPV-driven mouse model of skin cancer. Weanalyzed HPV-induced epithelial hyperplasia and squamous cell carcinoma formation, as well asgrowth of tumors inoculated into the dermis, inmice lacking skin mast cells. Unexpectedly, the absence of mast cells had no effect on HPV-induced epithelial growth or angiogenesis, on growth kinetics of inoculated tumors, or on the immunological tumor micro-milieu. Thus, the conspicuous recruitment of mast cells into tumor tissues cannot necessarily be equated with important mast cell functions in tumor growth.

Inhibition of bcl-2 and cox-2 Protein Expression after Local Application of a New Carmustine-Loaded Clinoptilolite-Based Delivery System in a Chemically Induced Skin Cancer Model in Mice.

Our research has focused on in vitro and in vivo evaluations of a new Carmustine (BCNU)-loaded clinoptilolite-based delivery system. Two clinoptilolite ionic forms—hydrogen form (HCLI) and sodium form (NaCLI)—were prepared, allowing a loading degree of about 5–6 mg BCNU/g of zeolite matrix due to the dual porous feature of clinoptilolite. Clinoptilolite-based delivery systems released 35.23% of the load in 12 h for the BCNU@HCLI system and only 10.82% for the BCNU@NaCLI system. The BCNU@HCLI system was chosen to develop gel and cream semisolid dosage forms. The cream (C_BCNU@HCLI) released 29.6% of the loaded BCNU after 12 h in the Nylon synthetic membrane test and 31.6% in the collagen membrane test, higher by comparison to the gel. The new cream was evaluated in vivo in a chemically induced model of skin cancer in mice. Quantitative immunohistochemistry analysis showed stronger inhibition of B-cell lymphoma-2 (bcl-2) and cyclooxygenase 2 (cox-2) protein expression, known markers for cancer survival and aggressiveness, after the treatment with C_BCNU@HCLI by comparison to all the control treatment types, including an off-label magistral formula commercially available Carmustine cream as reference, bringing evidence that a clinoptilolite-based delivery systems could be used as a cancer drug carriers and controlled release systems (skin-targeted topical delivery systems).

Bryostatin 1 causes attenuation of TPA‑mediated tumor promotion in mouse skin.

The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2‑diphenyl‑1‑picrylhydrazyl (DPPH) bleach invitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30µM doses of bryostatin1. Invivo, bryostatin1 prevented the TPA‑mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue. Pretreatment of the mice with bryostatin 1 (30µM) followed by administration of TPA reduced the edema, as demonstrated via punched‑out mouse ear tissue, to 7.2mg, compared with 14mg in the TPA‑treated group. Treatment with bryostatin 1 prior to TPA administration markedly prevented the inflammation of the skin by inhibiting hyperplasia in the epidermal layer and the aggregation of inflammatory cells. The results demonstrated that treatment of mice with bryostatin1 at a 30µM dose prior to TPA administration significantly (P<0.005) inhibited the TPA‑mediated increase in the level of COX‑2. The activity of ornithine decarboxylase, increased by TPA, was additionally inhibited following pretreatment of the mice with bryostatin 1. In the mice treated with bryostatin 1 at 30µM doses prior to the administration of TPA, the appearance of papillomas was 20%, compared with 100% in the TPA group. Mice pretreated with bryostatin 1 at 30µM doses prior to TPA administration exhibited the appearance of 0.4 mean papillomas in each animal, compared with 5.2 in the TPA group. Therefore, the results of the present study demonstrated that bryostatin 1 inhibited the development and progression of tumors of skin in the mice, through the prevention of inflammation‑inducing processes and the quenching of radicals. Therefore, bryostatin1 maybe considered to be adrug of importance in the treatment of skin tumor.

Investigating Ornithine Decarboxylase Posttranscriptional Regulation Via a Pulldown Assay Using Biotinylated Transcripts.

Ornithine decarboxylase (ODC) is the first rate-limiting enzyme in the polyamine biosynthetic pathway. It has been well documented that ODC is tightly regulated at the levels of transcription, posttranscriptional changes in RNA, and protein degradation during normal conditions and that these processes are dysregulated during tumorigenesis. Moreover, it has been recently shown that ODC is posttranscriptionally regulated by RNA binding proteins (RBPs) which can bind to the ODC mRNA transcript and alter its stability and translation. Using a mouse skin cancer model, we show that the RBP human antigen R (HuR) is able to bind to synthetic mRNA transcripts through a pulldown assay which utilizes a biotin-labeled ODC 3'-untranslated region (UTR). The details of this method are described here. A better understanding of the mechanism(s) which regulates ODC is critical for targeting ODC in chemoprevention.

The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis

CDK4 is crucial for G1-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cyclins are pivotal for the timely and unidirectional progression of cell cycle. However, how CDK4 itself is modulated by ubiquitin-mediated degradation has been elusive. Here we report that the steady-state level of CDK4 is controlled by PAQR4, a member of the progestin and adipoQ receptor family, and SKP2, an E3 ubiquitin ligase. Knockdown of PAQR4 leads to reduction of cell proliferation, accompanied by reduced protein level of CDK4. PAQR4 reduces polyubiquitination and degradation of CDK4. PAQR4 interacts with the C-terminal lobe of CDK4. On the other hand, SKP2 also interacts with the C-terminal lobe of CDK4 and enhances polyubiquitination and degradation of CDK4. Importantly, PAQR4 and SKP2 bind to the same region in CDK4, and PAQR4 competes with SKP2 for the binding, thereby abrogating SKP2-mediated ubiquitination of CDK4. Using a two-stage DMBA/TPA-induced skin cancer model, we find that PAQR4-deleted mice are resistant to chemical carcinogen-induced tumor formation. Collectively, our findings reveal that the steady-state level of CDK4 is controlled by the antagonistic actions between PAQR4 and SKP2, contributing to modulation of cell proliferation and tumorigenesis.

The parathyroid hormone regulates skin tumour susceptibility in mice

Using a forward genetics approach to map loci in a mouse skin cancer model, we previously identified a genetic locus, Skin tumour modifier of MSM 1 (Stmm1) on chromosome 7, conferring strong tumour resistance. Sub-congenic mapping localized Parathyroid hormone (Pth) in Stmm1b. Here, we report that serum intact-PTH (iPTH) and a genetic polymorphism in Pth are important for skin tumour resistance. We identified higher iPTH levels in sera from cancer-resistant MSM/Ms mice compared with susceptible FVB/NJ mice. Therefore, we performed skin carcinogenesis experiments with MSM-BAC transgenic mice (PthMSM-Tg) and Pth knockout heterozygous mice (Pth+/−). As a result, the higher amounts of iPTH in sera conferred stronger resistance to skin tumours. Furthermore, we found that the coding SNP (rs51104087, Val28Met) localizes in the mouse Pro-PTH encoding region, which is linked to processing efficacy and increased PTH secretion. Finally, we report that PTH increases intracellular calcium in keratinocytes and promotes their terminal differentiation. Taken together, our data suggest that Pth is one of the genes responsible for Stmm1, and serum iPTH could serve as a prevention marker of skin cancer and a target for new therapies.

Combination cisplatin and sulforaphane treatment reduces proliferation, invasion, and tumor formation in epidermal squamous cell carcinoma.

Epidermal squamous cell carcinoma is an extremely common type of cancer. Early tumors can be successfully treated by surgery, but recurrent disease is aggressive and resistant to therapy. Cisplatin is often used as a treatment, but the outcome is rarely satisfactory. For this reason new strategies are required. Sulforaphane is a diet-derived cancer prevention agent that is effective in suppressing tumor growth in animal models of skin cancer. We monitored the efficacy of sulforaphane and cisplatin as a combined therapy for squamous cell carcinoma. Both agents suppress cell proliferation, growth of cancer stem cell spheroids, matrigel invasion and migration of SCC-13 and HaCaT cells, and combination treatment is more efficient. In addition, SCC-13 cell derived cancer stem cells are more responsive to these agents than non-stem cancer cells. Both agents suppress tumor formation, but enhanced suppression is observed with combined treatment. Moreover, both agents reduce the number of tumor-resident cancer stem cells. SFN treatment of cultured cells or tumors increases apoptosis and p21Cip1 level, and both agents increase tumor apoptosis. We suggest that combined therapy with sulforaphane and cisplatin is efficient in suppressing tumor formation and may be a treatment option for advanced epidermal squamous cell carcinoma.

Effective Skin Cancer Treatment by Topical Co-delivery of Curcumin and STAT3 siRNA Using Cationic Liposomes.

The aim of the present study was to evaluate the effectiveness of iontophoretic co-delivery of curcumin and anti-STAT3 siRNA using cationic liposomes against skin cancer. Curcumin was encapsulated in DOTAP-based cationic liposomes and then complexed with STAT3 siRNA. This nanocomplex was characterized for the average particle size, zeta-potential, and encapsulation efficiency. The cell viability studies in B16F10 mouse melanoma cells have shown that the co-delivery of curcumin and STAT3 siRNA significantly (p<0.05) inhibited the cancer cell growth compared with either liposomal curcumin or STAT3 siRNA alone. The curcumin-loaded liposomes were able to penetrate up to a depth of 160μm inside the skin after iontophoretic (0.47mA/cm2) application. The in vivo efficacy studies were performed in the mouse model of melanoma skin cancer. Co-administration of the curcumin and STAT3 siRNA using liposomes significantly (p<0.05) inhibited the tumor progression as measured by tumor volume and tumor weight compared with either liposomal curcumin or STAT3 siRNA alone. Furthermore, the iontophoretic administration of curcumin-loaded liposome-siRNA complex showed similar effectiveness in inhibiting tumor progression and STAT3 protein suppression compared with intratumoral administration. Taken together, cationic liposomes can be utilized for topical iontophoretic co-delivery of small molecule and siRNA for effective treatment of skin diseases.

Photodynamic therapeutic efficacy of symmetrical diiodinated squaraine in in vivo skin cancer models

BackgroundPhotodynamic therapy (PDT) has clinical approval for use as a minimally invasive therapeutic procedure that is able to exert selective cytotoxic activity toward malignant cells. The dye selected for our study, symmetrical diiodinated squaraine, is one of the newly developed photosensitizers. The study is designed to determine the efficacy of PDT mediated by symmetrical diiodinated squaraine in skin tumor induced Swiss albino mice. MethodsSkin tumor was induced in mice with dimethyl benzanthracene (DMBA) and croton oil. After squaraine administration to the tumor mice, photodynamic treatment of tumors was performed using a 1000W halogen lamp corresponding to the light dose of 100J/cm2. The mice were euthanized and skin flaps and tumor tissues from the back of mice were excised for biochemical studies. The biochemical parameters analyzed include some relevant tumor markers for epithelial tissues, inflammatory markers and markers of apoptosis. The gene expression studies were done by RT-PCR. ResultsAfter two weeks of the treatment, there was significant inflammation. However at 90days after PDT, the parameters reverted to near-normal values. All marker parameters of tumor progression brought back to normal levels by PDT. Increased caspase-3 activity in PDT treated group shows that cell death might have occurred by apoptosis. The gene expression profile confirms the results. ConclusionsThe results of the whole study show the therapeutic efficacy and apoptosis mediated tumor destruction by squaraine PDT.

Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases

Pterostilbene is a naturally occurring analog of resveratrol with many health benefits. These health benefits are associated with its antioxidant activity, anti-inflammatory effects, and chemopreventive effects attributed to its unique structure. The skin cancer chemopreventive potential of pterostilbene is supported by a variety of mechanistic studies confirming the anti-inflammatory effects in skin cancer models. Molecular biological studies have identified that pterostilbene targets pleotropic signaling pathways, including those involved in mitogenesis, cell cycle regulation, and apoptosis. Recently, pterostilbene has been reported to induce autophagy in cancer and normal cells. Through autophagy induction, the inflammatory-related skin diseases can be attenuated. This finding suggests the potential use of pterostilbene in the treatment and prevention of skin disorders via alleviating inflammatory responses by autophagy induction. This review summarizes the protective and therapeutic benefits of pterostilbene in skin diseases from the viewpoint of its antioxidant, anti-inflammatory, and autophagy-inducing effects. Novel underlying mechanisms regarding these effects are discussed. We proposed that pterostilbene, a promising natural product, can be used as a preventive and therapeutic agent for inflammation-related skin disorders through induction of autophagy.

Experimental Basosquamous Carcinoma Model in Rats

Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumorigenesis in conventional furred mouse models by acting on hair follicle stem cells. In this work, we have developed a simple and convenient rat model of basosquamous carcinoma (BSC) using DMBA-induced carcinogenesis in male specific pathogen free (SPF) Wistar rats with no additional tumor promoter agents. The results showed that topical application of 0.1% solution of DMBA in benzene in a volume of 40 μL twice a week produced skin tumors after 8–9 months. As a result, during the 11–12th months, we obtained 15 animals with BSCs, 22 with basal cell carcinomas (BCCs), and 3 with squamous cell carcinomas (SCCs). This chemically driven skin cancer model in Wistar rats can serve as a suitable alternative to the mouse skin cancer model and can be reliably replicated as demonstrated by the experiment.

Hyaluronate-Gold Nanorod/DR5 Antibody Complex for Noninvasive Theranosis of Skin Cancer.

Noninvasive transdermal delivery is a promising method with distinct advantages including patient compliance over other delivery routes. Here, hyaluronate-gold nanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex was developed for transdermal theranosis of skin cancer. The successful formation of the complex was corroborated by 1H nuclear magnetic resonance, UV-vis spectroscopy, dynamic light scattering, zeta potential, and transmission electron microscopy. In vitro biological activity of the complex was verified by ELISA and MTT assay using HCT116 cancer cells. In addition, in vivo photoacoustic imaging and two-photon microscopy clearly visualized the transdermal delivery of HA-AuNR/DR5 Ab complex through the inevitable barrier of stratum corneum in the skin. Furthermore, in vivo antitumor effect on skin cancer model mice was confirmed from statistically significant decrease of tumor-reflecting luciferase expression levels and apoptotic signals in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Taken together, we could confirm the feasibility of HA-AuNR/DR5 Ab complex as a novel theranostic platform for noninvasive transdermal treatment of skin cancers.

Anti-Inflammatory Effects of Aspalathus linearis and Cyclopia spp. Extracts in a UVB/Keratinocyte (HaCaT) Model Utilising Interleukin-1α Accumulation as Biomarker

Ultraviolet B (UVB) radiation is one of the major predisposing risk factors of skin cancer. The anticancer and photoprotective effects of unoxidized rooibos (Aspalathus linearis) and honeybush (Cyclopia) herbal teas, containing high levels of dihydrochalones and xanthones, respectively, have been demonstrated in skin cancer models in vivo. In the current study, the anti-inflammatory effects of methanol and aqueous extracts of these herbal teas were investigated in a UVB/HaCaT keratinocyte model with intracellular interleukin-1α (icIL-1α) accumulation as a biomarker. Extracts of green tea (Camellia sinensis) served as benchmark. Both extracts of green tea and rooibos, as well as the aqueous extract of C. intermedia, enhanced UVB-induced inhibition of cell viability, proliferation and induction of apoptosis, facilitating the removal of icIL-1α. The underlying mechanisms may involve mitochondrial dysfunction exhibiting pro-oxidant responses via polyphenol-iron interactions. The methanol extracts of honeybush, however, protected against UVB-induced reduction of cell growth parameters, presumably via antioxidant mechanisms that prevented the removal of highly inflamed icIL-1α-containing keratinocytes via apoptosis. The dual antioxidant and/or pro-oxidant role of the polyphenolic herbal tea constituents should be considered in developing preventive strategies against UVB-induced skin carcinogenesis. The indirect removal of UVB damaged keratinocytes by herbal tea extracts via apoptosis may find application in the prevention of photo-induced inflammation.