RESUMO
Ganoderma is classified as a top grade traditional Chinese medicine for promoting human health by regulating 'vital energy'. Its potency towards metabolism and energy homeostasis, particularly, metabolic adaptations of adipocytes, needs to be re-evaluated through an evidence-based study. Here, the triterpenoid-rich Ganoderma tsugae ethanol extract (GTEE) was found to contribute towards adipogenesis accompanied with elevated intracellular lipid metabolic flux. Additionally, proteomic profiling revealed GTEE-upregulated mitochondrial remodeling and chemical energy redox modifications, which display UCP1-positive browning fat-selective features and a NADH-mediated adaptive mechanism. GTEE-treated mice with diet-induced obesity also resulted in the amelioration of white adipocyte hypertrophy and the appearance of UCP1-positive browning adipocytes. Our novel findings unravel that GTEE could promote intracellular metabolic flexibility and plasticity followed by the induction of adipocyte browning.
Assuntos
Adipogenia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Proteínas Fúngicas/metabolismo , Ganoderma/metabolismo , Proteômica , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Animais , Western Blotting , Dieta , Medicamentos de Ervas Chinesas/química , Eletroforese em Gel Bidimensional , Etanol/química , Ganoderma/química , Masculino , Camundongos , NAD/metabolismo , Obesidade/prevenção & controle , Biogênese de Organelas , Oxirredução , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Proteína Desacopladora 1/metabolismoRESUMO
Ganoderma, also known as Lingzhi or Reishi, has been used for medicinal purposes in Asian countries for centuries. It is a medicinal fungus with a variety of biological properties including immunomodulatory and antitumor activities. In this study, we investigated the molecular mechanisms by which Ganoderma tsugae (GT), one of the most common species of Ganoderma, inhibits the proliferation of HER2-overexpressing cancer cells. Here, we show that a quality assured extract of GT (GTE) inhibited the growth of HER2-overexpressing cancer cells in vitro and in vivo and enhanced the growth-inhibitory effect of antitumor drugs (e.g., taxol and cisplatin) in these cells. We also demonstrate that GTE induced cell cycle arrest by interfering with the HER2/PI3K/Akt signaling pathway. Furthermore, GTE curtailed the expression of the HER2 protein by modulating the transcriptional activity of the HER2 gene and the stability/degradation of the HER2 protein. In conclusion, this study suggests that GTE may be a useful adjuvant therapeutic agent in the treatment of cancer cells that highly express HER2.
RESUMO
Triptolide (TPL) inhibits the proliferation of a variety of cancer cells and has been proposed as an effective anticancer agent. In this study, we demonstrate that TPL downregulates HER2 protein expression in oral, ovarian, and breast cancer cells. It suppresses HER2 protein expression in a dose- and time-dependent manner. Transrepression of HER2 promoter activity by TPL is also observed. The interacting site of TPL on the HER2 promoter region is located between -207 and -103 bps, which includes a putative binding site for the transcription factor NF-κB. Previous reports demonstrated that TPL suppresses NF-κB expression. We demonstrate that overexpression of NF-κB rescues TPL-mediated suppression of HER2 promoter activity and protein expression in NIH3T3 cells and ovarian cancer cells, respectively. In addition, TPL downregulates the activated (phosphorylated) forms of HER2, phosphoinositide-3 kinase (PI3K), and serine/threonine-specific protein kinase (Akt). TPL also inhibits tumor growth in a mouse model. Furthermore, TPL suppresses HER2 and Ki-67 expression in xenografted tumors based on an immunohistochemistry (IHC) assay. These findings suggest that TPL transrepresses HER2 and suppresses the downstream PI3K/Akt-signaling pathway. Our study reveals that TPL can inhibit tumor growth and thereby may serve as a potential chemotherapeutic agent.
RESUMO
We examined the anti-angiogenic effects of Ganoderma tsugae methanol extract (GTME) on human epidermoid carcinoma A-431 cells. Our data indicate that GTME inhibits the expression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in vitro and in vivo, and also inhibits the capillary tube formation of human umbilical vein endothelial cells (HUVECs). We also show that the suppression of VEGF expression by GTME can be restored by treatment with EGF. These results suggest that GTME inhibits VEGF expression via the suppression of EGFR expression, resulting in the downregulation of VEGF secretion from epidermoid carcinoma A-431 cells. These findings reveal a novel role for G. tsugae in inhibiting EGFR and VEGF expression, which are important for tumor angiogenesis and growth. Thus, GTME may provide a potential therapeutic approach for anti-tumor treatment.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Células Escamosas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Receptores ErbB/biossíntese , Ganoderma/química , Proteínas de Neoplasias/biossíntese , Neovascularização Patológica/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Neoplasias Cutâneas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/transplante , Células Cultivadas/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Endotélio Vascular/citologia , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/genética , Receptores ErbB/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metanol , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Reishi , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma, known as Lingzhi or Reishi, has been traditionally administered throughout Asia for centuries as a cancer treatment and for other medicinal purposes. AIM OF THE STUDY: To investigate the inhibitory activity and explore the molecular mechanisms of anti-tumor effect on colorectal cancer cells in vitro and in vivo as well as to test the side effects of Ganoderma tsugae. MATERIALS AND METHODS: Methanol fraction was obtained from dried fruiting bodies of Ganoderma. TLC and HPLC were performed to differentiate and confirm the identification of different species as well as to quantify the bioactive molecules in methanol extracts of Ganoderma species. MTT and Trypan blue exclusion assay as well as tumorigenesis study were used to assess the anti-tumor effect in vitro and in vivo. Using flow cytometry and Western Blots, we examined further the molecular mechanisms of anti-tumor effect. Finally, biochemical and hematological profiles and pathological examinations were used to evaluate the safety. RESULTS: The Ganoderma tsugae extracts inhibit colorectal cancer cell proliferation caused by accumulating cells in G(2)/M phase, and it may be through downregulation of cyclin A and B1 and upregulation of p21 and p27. Tumorigenesis study in nude mice revealed the extracts caused tumor shrinkage. Additionally, safety assay showed Ganoderma tsugae extracts caused no significant side effects in an animal model. CONCLUSIONS: This study provides molecular evidence that Ganoderma tsugae extracts exert anti-tumor effects both in vitro and in vivo on colorectal adenocarcinoma cells by inducing G(2)/M cell cycle arrest. More importantly, no significant physiological changes resulting from treatment with Ganoderma tsugae extracts were observed in the animal model. Therefore, these data provide new insights into the possible therapeutic use of Ganoderma tsugae for treating colorectal cancer.