RESUMO
Ultraviolet Beam (UVB) radiation is the main cause of skin cancer worldwide. Besides biocompatibility, the instability and limited skin permeability are the most challenging features of many effective photochemopreventive agents. (-)-Epigallocatechin-3-gallate (EGCG) is a natural polyphenolic compound extracted from Camellia sinensis that has been demonstrated to have antioxidant, anti-inflammatory, and anti-cancer properties. We evaluated the efficacy of three innovative EGCG nanoformulations in chemoprevention of UVB-induced DNA damage in keratinocytes. Results indicated that the EGCG nanoformulations reduced UVB-induced oxidative stress elevation and DNA damage. The nanoformulations also reduced the UVB-induced formation of pyrimidine and pyrimidone photoproducts in 2D human immortalized HaCaT keratinocytes and SKH-1 hairless mice through antioxidant effects and possibly through absorption of UVB radiation. In addition, EGCG nanoformulations inhibited UVB-induced chemokine/cytokine activation and promoted EGCG skin permeability and stability. Taken together, the results suggest the use of EGCG nanoformulations as potential natural chemopreventive agents during exposure to UVB radiation.
Assuntos
Catequina , Animais , Antioxidantes/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Dano ao DNA , Humanos , Queratinócitos , Camundongos , Camundongos Pelados , Pele , Raios UltravioletaRESUMO
Living host system possess mechanisms like innate immune system to combat against inflammation, stress singling, and cancer. These mechanisms are initiated by PAMP and DAMP mediated recognition by PRR. PRR is consist of variety of nucleic acid sensors like-RNA sensors. They play crucial role in identifying exogenous and endogenous RNA molecules, which subsequently mediate pro/inflammatory cytokine, IFN and ISGs response in traumatized or tumorigenic conditions. The sensors can sensitize wide range of nucleic acid particle in term of size and structure, while each category sensors belongs subclasses with differentially expressed in cell and distinguished functioning mechanisms. They are also able to make comparison between self and non-self-nucleic acid molecules through specific mechanisms. Besides exhibiting anti-inflammatory and anti-tumorigenic responses, RNA sensors cover the broad spectrum of response mechanisms. Transcriptionally RNA sensors undergo with tight epigenetic regulations. In this review study, we will be going to discuss about the details of RNA sensors, their functional mechanisms and epi-transactional regulations.
Assuntos
Ácidos Nucleicos , RNA , Epigênese Genética , Humanos , Imunidade Inata/genética , Inflamação , RNA/genéticaRESUMO
Many dietary polyphenols have been investigated for their therapeutic potential either as single agents or in combinations. Despite the significant anticancer potential of these polyphenols in in vitro cell culture and in vivo animal models, their clinical applications have been limited because of challenges such as ineffective systemic delivery, stability and low bioavailability. Nanoencapsulation of these polyphenols could prolong circulation, improve localization, enhance efficacy and reduce the chances of multidrug resistance. This review summarized the use of various polyphenols especially epigallocatechin gallate, quercetin, curcumin and resveratrol as nanoformulations for cancer prevention and treatment. Despite some success, more research is warranted to design a nanoencapsulated combination of polyphenols, effective in in vitro, in vivo and human systems.
Assuntos
Catequina , Curcumina , Neoplasias , Animais , Catequina/farmacologia , Curcumina/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Polifenóis/farmacologia , Quercetina , ResveratrolRESUMO
Psoriasis is a chronic immune-mediated skin disease that involves the interaction of immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation, and angiogenesis. Because the available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can repair the molecular defects associated with psoriasis and could possibly be developed for its management. Fisetin (3,7,3',4'-tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables, has demonstrated proapoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological, and tissue engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC), and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose- and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α stimulated NHEKs also significantly inhibited the activation of p38 and JNK, but had enhanced effect on ERK1/2 (MAPK). In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFN-γ and IL-17A by 12-O-tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in vivo human psoriatic skin lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify the prodifferentiative, antiproliferative, and anti-inflammatory effects of fisetin, via modulation of the PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin models of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.
Assuntos
Flavonoides/farmacologia , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Flavonóis , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Psoríase/metabolismo , Psoríase/patologia , Pele/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Growth factor receptor-binding protein 10 (GRB10) is a well-known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt-targeted therapies in prostate cancer (PCa) is loss of mTOR-regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)-deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild-type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild-type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K-driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer.-Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma.
Assuntos
Proteína Adaptadora GRB10/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Carcinógenos/antagonistas & inibidores , Carcinógenos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteína Adaptadora GRB10/antagonistas & inibidores , Proteína Adaptadora GRB10/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Modelos Biológicos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/genética , RNA Mensageiro , Transdução de SinaisRESUMO
Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology, including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone-modulating enzymes, resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin-related events is essential. Here, we report that AKT inhibition in prostate-specific PTEN knockout mice significantly induces di- and trimethylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation-specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Furthermore, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition-mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors.
Assuntos
Histona Desmetilases com o Domínio Jumonji/genética , MicroRNAs/genética , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Fosforilcolina/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Proteínas Repressoras/genética , Acetilação/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Masculino , Metilação/efeitos dos fármacos , Camundongos , Fosforilcolina/administração & dosagem , Fosforilcolina/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Psoriasis is a chronic and currently incurable inflammatory skin disease characterized by hyperproliferation, aberrant differentiation, and inflammation, leading to disrupted skin barrier function. The use of natural agents that can abrogate these effects could be useful for the treatment of psoriasis. Earlier studies have shown that treatment of keratinocytes and mouse skin with the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) mitigated inflammation and increased the expression of caspase-14 while promoting epidermal differentiation and cornification. However, bioavailability issues have restricted the development of EGCG for the treatment of psoriasis. MATERIALS AND METHODS: To overcome these limitations, we employed a chitosan-based polymeric nanoparticle formulation of EGCG (CHI-EGCG-NPs, hereafter termed nanoEGCG) suitable for topical delivery for treating psoriasis. We investigated and compared the efficacy of nanoEGCG versus native or free EGCG in vitro and in an in vivo imiquimod (IMQ)-induced murine psoriasis-like dermatitis model. The in vivo relevance and efficacy of nanoEGCG formulation (48 µg/mouse) were assessed in an IMQ-induced mouse psoriasis-like skin lesion model compared to free EGCG (1 mg/mouse). RESULTS: Like free EGCG, nanoEGCG treatment induced differentiation, and decreased proliferation and inflammatory responses in cultured keratinocytes, but with a 4-fold dose advantage. Topically applied nanoEGCG elicited a significant (p<0.01) amelioration of psoriasiform pathological markers in IMQ-induced mouse skin lesions, including reductions in ear and skin thickness, erythema and scales, proliferation (Ki-67), infiltratory immune cells (mast cells, neutrophils, macrophages, and CD4+ T cells), and angiogenesis (CD31). We also observed increases in the protein expression of caspase-14, early (keratin-10) and late (filaggrin and loricrin) markers of differentiation, and the activator protein-1 factor (JunB). Importantly, a significant modulation of several psoriasis-related inflammatory cytokines and chemokines was observed compared to the high dose of free EGCG (p<0.05). Taken together, topically applied nanoEGCG displayed a >20-fold dose advantage over free EGCG. CONCLUSION: Based on these observations, our nanoEGCG formulation represents a promising drug-delivery strategy for treating psoriasis and possibly other inflammatory skin diseases.
Assuntos
Aminoquinolinas/toxicidade , Catequina/análogos & derivados , Quitosana/química , Dermatite/prevenção & controle , Queratinócitos/metabolismo , Nanopartículas/administração & dosagem , Psoríase/prevenção & controle , Administração Tópica , Animais , Antineoplásicos/toxicidade , Antioxidantes/química , Antioxidantes/farmacologia , Catequina/química , Catequina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dermatite/etiologia , Proteínas Filagrinas , Humanos , Imiquimode , Queratinócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Psoríase/induzido quimicamenteRESUMO
We recently identified and characterized nummularic acid (NA) as a major chemical constituent of Fraxinus xanthoxyloides, a medicinal plant used for over hundred years in traditional medicine. In this study, we describe its potential anti-cancer activity using prostate cancer (PCa) cells as a model. We found that NA treatment (5-60 µM) significantly reduced the proliferation and colony formation capabilities of PCa DU145 and C4-2 cells in a time and dose dependent manner, reduced the migratory and invasive properties and increased apoptotic cell population. Mechanistically, we found that NA treatment to PCa cells resulted in a sustained activation of adenosine monophosphate-activated protein kinase (AMPK). NA simultaneously increased acetyl CoA carboxylase phosphorylation and decreased pS6 phosphorylation, the two major substrates of AMPK. Further, NA treatment significantly elevated the cellular ADP/ATP ratio and altered glycolytic rate. We further observed a reversible decrease in oxygen consumption rate in NA treated cells when compared to the control. Finally, we performed global untargeted metabolomics which showed that NA treatment alters PCa cell metabolism at multiple sites including glycolysis, tricarboxylic acid, and glutamine metabolism which supported our observation of a possible AMPK activation. In summary, we report NA as a novel small molecule activator of AMPK that alters cellular metabolism to induce energy crisis and ultimately cancer cell death. Because of its unique mechanism NA could be potentially applicable against other cancer types.
Assuntos
Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fraxinus/química , Plantas Medicinais/química , Triterpenos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Metabolômica/métodos , Estrutura Molecular , Peptídeos Cíclicos , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Triterpenos/químicaRESUMO
Tumor masses are deprived of oxygen and characterized by enhanced glucose uptake followed by glycolysis. Elevated glucose levels induce non-enzymatic glycosylation or glycation of proteins which leads to accumulation of advanced glycation end products (AGE). These AGE molecules bind to their respective receptors called the receptor for advanced glycation end products (RAGE) and initiate several aberrant signaling pathways leading to onset of diseases such as diabetes, Alzheimer's, atherosclerosis, heart failure and cancer. The role of AGE in cancer progression is being extensively studied in recent years. As cancer cells are hypoxic in nature and adapted to glycolysis, which induces glycation, its effects need to be understood in greater detail. Since AGE-RAGE signaling is involved in cancer progression, inhibition of AGE-RAGE interaction could be a potential therapeutic target. The purpose of this review is to highlight the role of AGE-RAGE interaction in hypoxic cancer cells.
Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Glicosilação , Hipóxia/metabolismo , Animais , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Terapia de Alvo Molecular , Ligação Proteica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Tumorigenesis and epigenetic are closely linked with each other. Epigenetic changes are potential regulators of gene expression without involving any change in the DNA itself. More interestingly, epigenetic changes are reversible heritable changes which pass through generations. Many dietary bioactive ingredients regulate epigenetic control of cells and influence biochemical processes. Correlation between epigenetic regulation and cancer onset has been well established. Recent studies provide important information on the role of bioactive dietary components in cancer prevention and therapy. Several bioactive components are responsible for modification of the epigenome by affecting DNA methylation, histone modification, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs). This review summarizes recent advancements in this field and describes the role of many bioactive components in regulating human epigenome and how these modifications can be exploited for prevention and treatment of cancer.
Assuntos
Dieta , Epigênese Genética , Neoplasias/genética , Nutrientes/farmacologia , Animais , Humanos , Neoplasias/terapia , Nutrientes/uso terapêuticoRESUMO
Earlier we introduced the concept of 'nanochemoprevention' i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention. Here, we extended our work and developed polymeric EGCG-encapsulated nanoparticles (NPs) targeted with small molecular entities, able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa), and evaluated their efficacy in preclinical studies. First, we performed a molecular recognition of DCL- and AG-PEGylation on ligand binding on PSMA active site. Next, the biocompatible polymers PLGA-PEG-A were synthesized and used as base to conjugate DCL or AG to obtain the respective copolymers, needed for the preparation of targeted NPs. The resulting EGCG encapsulating NPs led to an enhanced anti-proliferative activity in PCa cell lines compared to the free EGCG. The behavior of EGCG encapsulated in NPs in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor, using EGCG-loaded NPs, with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of target-specific enhanced bioavailability and limited unwanted toxicity, thus leading to a significant potential for probable clinical outcome.
Assuntos
Anticarcinógenos/administração & dosagem , Catequina/análogos & derivados , Portadores de Fármacos , Composição de Medicamentos , Nanopartículas , Animais , Anticarcinógenos/química , Apoptose/efeitos dos fármacos , Catequina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Cinética , Ligantes , Masculino , Camundongos , Conformação Molecular , Terapia de Alvo Molecular , Nanopartículas/química , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis. RESULTS: A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2ß/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.
Assuntos
Antocianinas/farmacologia , Antioxidantes/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Psoríase/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Tópica , Aminoquinolinas/efeitos adversos , Animais , Antocianinas/administração & dosagem , Antocianinas/química , Antioxidantes/administração & dosagem , Antioxidantes/química , Sítios de Ligação , Biópsia , Quimiotaxia de Leucócito , Citocinas/metabolismo , Modelos Animais de Doenças , Imiquimode , Imunomodulação/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Psoríase/tratamento farmacológico , Psoríase/etiologia , Psoríase/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismoRESUMO
Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 µmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863-74. ©2016 AACR.
Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Flavonóis , Humanos , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Resultado do Tratamento , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We and others have shown previously that fisetin, a plant flavonoid, has therapeutic potential against many cancer types. Here, we examined the probable mechanism of its action in prostate cancer (PCa) using a global metabolomics approach. HPLC-ESI-MS analysis of tumor xenografts from fisetin-treated animals identified several metabolic targets with hyaluronan (HA) as the most affected. Efficacy of fisetin on HA was then evaluated in vitro and also in vivo in the transgenic TRAMP mouse model of PCa. Size exclusion chromatography-multiangle laser light scattering (SEC-MALS) was performed to analyze the molar mass (Mw) distribution of HA. Fisetin treatment downregulated intracellular and secreted HA levels both in vitro and in vivo Fisetin inhibited HA synthesis and degradation enzymes, which led to cessation of HA synthesis and also repressed the degradation of the available high-molecular-mass (HMM)-HA. SEC-MALS analysis of intact HA fragment size revealed that cells and animals have more abundance of HMM-HA and less of low-molecular-mass (LMM)-HA upon fisetin treatment. Elevated HA levels have been shown to be associated with disease progression in certain cancer types. Biological responses triggered by HA mainly depend on the HA polymer length where HMM-HA represses mitogenic signaling and has anti-inflammatory properties whereas LMM-HA promotes proliferation and inflammation. Similarly, Mw analysis of secreted HA fragment size revealed less HMM-HA is secreted that allowed more HMM-HA to be retained within the cells and tissues. Our findings establish that fisetin is an effective, non-toxic, potent HA synthesis inhibitor, which increases abundance of antiangiogenic HMM-HA and could be used for the management of PCa.
Assuntos
Flavonoides/administração & dosagem , Ácido Hialurônico/metabolismo , Neoplasias da Próstata/prevenção & controle , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonóis , Receptores de Hialuronatos/fisiologia , Masculino , Camundongos , Peso Molecular , Neoplasias da Próstata/metabolismoRESUMO
The last few decades have seen a resurgence of interest among the scientific community in exploring the efficacy of natural compounds against various human cancers. Compounds of plant origin belonging to different groups such as alkaloids, flavonoids and polyphenols evaluated for their cancer preventive effects have yielded promising data, thereby offering a potential therapeutic alternative against this deadly disease. The flavonol fisetin (3,3',4',7-tetrahydroxyflavone), present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant and more significantly anti-carcinogenic activity when assessed in diverse cell culture and animal model systems. The purpose of this review is to update and discuss key findings obtained till date from in vitro and in vivo studies on fisetin, with special focus on its anti-cancer role. The molecular mechanism(s) described in the observed growth inhibitory effects of fisetin in different cancer cell types is also summarized. Moreover, an attempt is made to delineate the direction of future studies that could lead to the development of fisetin as a potent chemopreventive/chemotherapeutic agent against cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/uso terapêutico , Flavonóis , Humanos , Terapia de Alvo Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
Cancer remains a major public health concern and a significant cause of death worldwide. Identification of bioactive molecules that have the potential to inhibit carcinogenesis continues to garner interest among the scientific community. In particular, flavonoids from dietary sources are the most sought after because of their safety, cost-effectiveness, and feasibility of oral administration. Emerging data have provided newer insights into understanding the molecular mechanisms that are essential to identify novel mechanism-based strategies for cancer prevention and treatment. Dietary flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) found in many fruits and vegetables has been shown in preclinical studies to inhibit cancer growth through alteration of cell cycle, inducing apoptosis, angiogenesis, invasion, and metastasis without causing any toxicity to normal cells. Although data from in-vitro and in-vivo studies look convincing, well-designed clinical trials in humans are needed to conclusively determine the efficacy across various cancers. This review highlights the chemopreventive and therapeutic effects, molecular targets, and mechanisms that contribute to the observed anticancer activity of fisetin against various cancers.
Assuntos
Anticarcinógenos/farmacologia , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Quimioprevenção , Feminino , Flavonóis , Frutas/química , Humanos , Masculino , Polifenóis/farmacologia , Verduras/químicaAssuntos
Aminoquinolinas/farmacologia , Psoríase/induzido quimicamente , Psoríase/metabolismo , Animais , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/metabolismo , Imiquimode , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Regulação para CimaRESUMO
Epidemiologic studies indicated that diabetics treated with metformin had a lower incidence of cancer than those taking other anti-diabetes drugs. This led to a surge in the efforts for identification of safer and more effective metformin mimetic compounds. The plant Ficus microcarpa is widely used for the treatment of type 2 diabetes in traditional medicine in South Asia. We obtained extracts from this plant and identified a small molecule, plectranthoic acid (PA), with potent 5'AMP-activated kinase (AMPK) activating properties far superior than metformin. AMPK is the central hub of metabolic regulation and a well-studied therapeutic target for metabolic syndrome, type-2 diabetes and cancer. We observed that treatment of prostate cancer (PCa) cells with PA inhibited proliferation and induced G0/G1 phase cell cycle arrest that was associated with up-regulation of cyclin kinase inhibitors p21/CIP1 and p27/KIP1. PA treatment suppressed mTOR/S6K signaling and induced apoptosis in PCa cells in an AMPK-dependent manner. Interestingly, PA-induced autophagy in PCa cells was found to be independent of AMPK activation. Combination studies of PA and metformin demonstrated that metformin had an inhibitory effect on PA-induced AMPK activation and suppressed PA-mediated apoptosis. Given the anti-proliferative role of PA in cancer and its potent anti-hyperglycemic activity, we suggest that PA should be explored further as a novel activator of AMPK for its ultimate use for the prevention of cancers and treatment of type 2 diabetes.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Extratos Vegetais/farmacologia , Neoplasias da Próstata/patologia , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/química , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ficus/química , Citometria de Fluxo , Humanos , Masculino , Simulação de Dinâmica Molecular , Extratos Vegetais/isolamento & purificação , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Conformação Proteica , Células Tumorais CultivadasRESUMO
Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies suggested that fisetin binds to ß-tubulin with superior affinity compared to paclitaxel. Fisetin treatment of human prostate cancer cells resulted in robust up-regulation of microtubule associated proteins (MAP)-2 and -4. In addition, fisetin treated cells were enriched in α-tubulin acetylation, an indication of stabilization of microtubules. Fisetin significantly inhibited PCa cell proliferation, migration, and invasion. Nudc, a protein associated with microtubule motor dynein/dynactin complex that regulates microtubule dynamics, was inhibited with fisetin treatment. Further, fisetin treatment of a P-glycoprotein overexpressing multidrug-resistant cancer cell line NCI/ADR-RES inhibited the viability and colony formation. Our results offer in vitro proof-of-concept for fisetin as a microtubule targeting agent. We suggest that fisetin could be developed as an adjuvant for treatment of prostate and other cancer types.