The medicinal mushroom Ganoderma lucidum prevents lung tumorigenesis induced by tobacco smoke carcinogens.

Ganoderma lucidum (GL), commonly known as "Lingzhi", is a well-known medicinal mushroom with antioxidant and anti-cancer activity. This study examined the effects of a commercial GL product (GLSF) containing the spore and fruiting body in a 30:8 ratio on tobacco smoke carcinogen-induced lung toxicity and carcinogenesis. The potential chemopreventive effect of GLSF was evaluated in vitro and in vivo. The non-tumorous human bronchial epithelial cells (BEAS-2B cells) were treated with GLSF extract (0.025 and 0.05 mg/mL), which significantly blocked malignant transformation induced by benzo[a]pyrene diol epoxide (BPDE) in a dose-dependent manner. To confirm its anti-carcinogenic activity in vivo, the mice were pre-treated with GLSF (2.0 g/kg of body weight) or curcumin (100 mg/kg of body weight) by oral gavage daily for 7 days and then exposed to a single dose of benzo[a]pyrene (B[a]P) (125 mg/kg of body weight). The GLSF-treated mice showed a significant reduction in B[a]P-induced lung toxicity, as indicated by decreased lactate dehydrogenase activity, malondialdehyde levels, inflammatory cell infiltration, and improved lung histopathology. We next determined the chemopreventive activity of GLSF in mice which were exposed to two weekly doses of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 100 mg/kg, on the 1st and 8th days) and fed with control or a modified diet containing GLSF (2.0 g/kg) or metformin (250 mg/kg) for 33 weeks. The GLSF and metformin treatments blocked NNK-induced lung tumor development by decreasing the lung weight, tumor area, and tumor burden compared to the mice exposed to NNK only. GLSF treatment also attenuated the expression of inflammatory, angiogenic, and apoptotic markers in lung tumors. Therefore, GLSF may be used for ameliorating tobacco smoke carcinogens-induced lung toxicity and carcinogenesis.

Report of multiple high-grade gliomas in two patients with shared retained ATRX, wild-type IDH, losses of CDKN2A genes and alterations in the PTEN-PI3K axis.

Solitary gliomas have been well described in the literature. Multiple gliomas, however, have not received the same notoriety, and as such further studies may be helpful in elucidating their unique clinicopathologic features and molecular basis. We present two patients, each with multiple high-grade gliomas, and describe their clinicopathologic and molecular characteristics in comparison with those reported in the literature in an attempt to better understand their shared tumorigenic mechanisms. Extensive molecular, FISH and genomic profiling studies detected multiple unique abnormalities in our two cases with shared molecular features of retained ATRX, wild-type IDH, losses of CDKN2A genes and alterations in the PTEN-PI3K Axis.

Transcriptome Sequencing Reveals the Mechanism behind Chemically Induced Oral Mucositis in a 3D Cell Culture Model.

Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find potential therapeutic targets. Here, we treated an organotypic 3D oral mucosal tissue model consisting of human keratinocytes grown on top of human fibroblasts with a high or low dose of everolimus for 40 or 60 h and investigated (1) the effect of everolimus on microscopic sections of the 3D cell culture for evidence of morphologic changes and (2) changes in the transcriptome by high throughput RNA-Seq analysis. We show that the most affected pathways are cornification, cytokine expression, glycolysis, and cell proliferation and we provide further details. This study provides a good resource towards a better understanding of the development of oral mucositis. It gives a detailed overview of the different molecular pathways that are involved in mucositis. This in turn provides information about potential therapeutic targets, which is an important step towards preventing or managing this common side effect of cancer treatment.

Transfersome Encapsulated with the R-carvedilol Enantiomer for Skin Cancer Chemoprevention.

The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the ß-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.

The ß-Blocker Carvedilol Prevents Benzo(a)pyrene-Induced Lung Toxicity, Inflammation and Carcinogenesis.

The current study evaluated the effects of the ß-blocker carvedilol on benzo(a)pyrene (B(a)P) and its active metabolite benzo(a)pyrene diol epoxide (BPDE)-induced lung toxicity, inflammation and carcinogenesis and explored the potential mechanisms. Carvedilol blocked the BPDE-induced malignant transformation of human bronchial epithelial cells BEAS-2B. In BEAS-2B cells, B(a)P strongly activated ELK-1, a transcription factor regulating serum response element (SRE) signaling, which was attenuated by carvedilol. Carvedilol also inhibited the B(a)P-induced AhR/xenobiotic responsive element (XRE) and mRNA expression of CYP1A1 and attenuated B(a)P-induced NF-κB activation. In a B(a)P-induced acute lung toxicity model in CD-1/IGS mice, pretreatment with carvedilol for 7 days before B(a)P exposure effectively inhibited the B(a)P-induced plasma levels of lactate dehydrogenase and malondialdehyde, inflammatory cell infiltration and histopathologic abnormalities in the lung, and upregulated the expression of GADD45α, caspase-3 and COX-2 in the lung. In a B(a)P-induced lung carcinogenesis model in A/J mice, carvedilol treatment for 20 weeks did not affect body weight but significantly attenuated tumor multiplicity and volume. These data reveal a previously unexplored role of carvedilol in preventing B(a)P-induced lung inflammation and carcinogenesis by inhibiting the cross-talk of the oncogenic transcription factors ELK-1, AhR and NF-κB.

The medicinal mushroom Ganoderma lucidum attenuates UV-induced skin carcinogenesis and immunosuppression.

The medicinal mushroom Ganoderma lucidum is traditionally used for treating multiple diseases, including cancer. This study examined skin cancer preventive activity of a commercial product containing spore and fruiting body in 30:8 ratio (GLSF). Extracts of GLSF and spore component (GLS) were prepared using artificial gastrointestinal juice and examined on JB6 cells. GLSF and GLS dose-dependently inhibited epidermal growth factor-induced JB6 transformation at non-toxic concentrations. SKH-1 mice which were fed with diets containing GLSF (1.25%), GLS (0.99%) or the fruiting body (GLF) (0.26%) were exposed to chronic low-dose ultraviolet (UV) radiation to assess their effects on skin carcinogenesis. GLSF, but not GLS or GLF, reduced skin tumor incidence and multiplicity. In non-tumor skin tissues of mice, GLSF attenuated UV-induced epidermal thickening, expression of Ki-67, COX-2 and NF-κB, while in tumor tissues, GLSF increased expression of CD8 and Granzyme B. To examine the effects of GLSF on UV-induced immunosuppression, mice which were fed with GLSF were evaluated for the contact hypersensitivity (CHS) response to dinitrofluorobenzene (DNFB). GLSF significantly reversed UV-mediated suppression of DNFB-induced CHS by increasing CD8+ and decreasing CD4+ and FoxP3+ T-cells in mouse ears. Therefore, GLSF prevents skin cancer probably via attenuating UV-induced immunosuppression.

Topical carvedilol delivery prevents UV-induced skin cancer with negligible systemic absorption.

The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10 µM) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25 weeks, topical T-CAR gel (10 µM) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100 µM), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32 mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects.

Prevention of Skin Carcinogenesis by the Non-ß-blocking R-carvedilol Enantiomer.

Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The ß-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent ß-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess ß-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of ß-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against UV-induced intracellular oxidative stress and release of prostaglandin E2 from the JB6 P+ cells. In an acute UV-induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1ß mRNA levels similar to carvedilol. In a chronic UV (50-150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis. PREVENTION RELEVANCE: In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-ß-blocking enantiomer present in the racemic ß-blocker, carvedilol. As R-carvedilol does not have ß-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of ß-blockers.

Inhibitory activity of medicinal mushroom Ganoderma lucidum on colorectal cancer by attenuating inflammation.

The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits an inhibitory effect on cancers. However, the underlying mechanism of the antitumor activity of GL is not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing a mixture of spores and fruiting bodies namely "GLSF", in colorectal carcinoma. We found that in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed a modified diet containing GLSF for 1 month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of the GLSF-down-regulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1ß, IL-11 and Cox-2. Pathway enrichment analysis suggested that several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. "Cancer" was the major significantly inhibited biological effect of GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppression of NF-κB-regulated inflammation and carcinogenesis.

Highly aggressive undifferentiated small round blue cell tumor of foot with unique SMARCA1, KAT6A and NAV3 mutations.

Malignancies characterized histologically by high-grade monotonous small round blue cells (SRBCs) belong to a heterogeneous group of neoplasms often referred to as Ewing family of tumors. The most common molecular confirmation of these neoplasms is by fusions between EWSR1 gene on chromosome 22 and the ETS family of transcription factors, including FLI1 gene (11q24) and the ERG (21q22), that are implicated in the development of different tissues as well as cancer progression. In this article, we present a case of highly aggressive extraskeletal SRBC tumor involving the foot of a 24-year-old male with sole molecular findings of mutations in KAT6A, NAV3 and SMARCA1 genes with high expression of soft tissue markers (COL1A1, COL1A2, COL3A1) and MYC mRNA. To our knowledge, this unique mutational pattern has not previously been described in SRBCs.