Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a ...broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response.
Ketone bodies beta-hydroxybutyrate (bHB) and acetoacetate are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP ...production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.
Fenofibrate, a well-known normolipidemic drug, has been shown to exert strong anticancer effects against tumors of neuroectodermal origin including glioblastoma. Although some pharmacokinetic studies ...were performed in the past, data are still needed about the detailed subcellular and tissue distribution of fenofibrate (FF) and its active metabolite, fenofibric acid (FA), especially in respect to the treatment of intracranial tumors. We used high performance liquid chromatography (HPLC) to elucidate the intracellular, tissue and body fluid distribution of FF and FA after oral administration of the drug to mice bearing intracranial glioblastoma. Following the treatment, FF was quickly cleaved to FA by blood esterases and FA was detected in the blood, urine, liver, kidney, spleen and lungs. We have also detected small amounts of FA in the brains of two out of six mice, but not in the brain tumor tissue. The lack of FF and FA in the intracranial tumors prompted us to develop a new method for intracranial delivery of FF. We have prepared and tested in vitro biodegradable poly-lactic-co-glycolic acid (PLGA) polymer wafers containing FF, which could ultimately be inserted into the brain cavity following resection of the brain tumor. HPLC-based analysis demonstrated a slow and constant diffusion of FF from the wafer, and the released FF abolished clonogenic growth of glioblastoma cells. On the intracellular level, FF and FA were both present in the cytosolic fraction. Surprisingly, we also detected FF, but not FA in the cell membrane fraction. Electron paramagnetic resonance spectroscopy applied to spin-labeled phospholipid model-membranes revealed broadening of lipid phase transitions and decrease of membrane polarity induced by fenofibrate. Our results indicate that the membrane-bound FF could contribute to its exceptional anticancer potential in comparison to other lipid-lowering drugs, and advocate for intracranial delivery of FF in the combined pharmacotherapy against glioblastoma.
ABSTRACT
The effects of feeding low nonphytate phosphorus (NPP) corn-soybean meal-based diets supplemented with myo-inositol at 0.1%, or with phytase B at 1,300 acid phosphatase units/kg, or with ...phytase B enriched in 6-phytase A at 300 phytase units/kg on the hematological indices and the α-1 acid glycoprotein (AGP) concentrations in the blood of Bovans Brown laying hens were investigated. The experimental design comprised also a negative control diet and an internal control diet that had the NPP content adjusted by the addition of 0.304 g of monocalcium phosphate per kg to reach the NPP level similar to that resulting from the combined action of both phytases. A total of sixty 50-wk-old hens were randomly assigned to the dietary treatments with 12 cage replicates of 1 hen, and fed the experimental diets until wk 62, when the blood samples were taken and analyzed for basic hematological indices and for AGP concentrations in sera. The hematological indices from all the experimental groups remained in a normal range; nevertheless, the statistically significant effects of diet on hemoglobin concentration (P = 0.003), erythrocyte counts (P = 0.035), the percentage of lymphocytes (P = 0.020), heterophils (P = 0.002), eosinophils (P = 0.023), and basophils (P = 0.001) in the leucocyte population, as well as on the heterophil to lymphocyte ratio (P = 0.003), were observed. The highest erythrocyte counts were characteristic for hens fed the diet supplemented with both phytase A and phytase B. The highest heterophil to lymphocyte ratios were found in blood of hens fed the diet supplemented with phytase B, whereas the highest basophil percentages and the highest AGP concentrations occurred in birds fed the negative control diet. A highly significant correlation was observed between AGP concentrations in sera and BW losses determined previously. The results indicate that the low-NPP corn soybean meal-based diets increased acute phase protein level in laying hens. Phytase B alone, and particularly in combination with phytase A, acted as a potent mediator of the response, whereas supplementary myo-inositol did not.
Melanins form a diverse group of pigments synthesized in living organisms in the course of hydroxylation and polymerization of organic compounds. Melanin production is observed in all large taxa from ...both Pro- and Eukaryota. The basic functions of melanins are still a matter of controversy and speculation, even though their adaptative importance has been proved. Melanogenesis has probably evolved parallel in various groups of free living organisms to provide protection from environmental stress conditions, but in pathogenic microorganisms it correlates with an increased virulence. The genes responsible for melanization are collected in some cases within operons which find a versatile application in genetic engineering. This review summarizes current views on melanogenesis in Pro- and Eukaryotic microorganisms in terms of their biotechnological and biomedical importance.
Inhibition of melanoma metastases by fenofibrate GRABACKA, Maja; PLACHA, Wojciech; PLONKA, Przemyslaw M ...
Archives of Dermatological Research,
07/2004, Letnik:
296, Številka:
2
Journal Article
Recenzirano
The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) alpha, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM ...Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR alpha in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.
During metastases, cancer cells are temporarily exposed to the condition in which interactions with extracellular environment can be restricted (anchorage-independence). We demonstrate that the ...sensitivity of prostate cancer cell lines, DU145 and PC-3, to genotoxic treatment (cisplatin and gamma-irradiation) increased several folds when cells were forced to grow in anchorage-independence. This enhanced drug sensitivity was associated with a severe impairment of homologous recombination-directed DNA repair (HRR). The mechanism involves Rad51, which is the major enzymatic component of HRR. The protein level of Rad51 and its recruitment to DNA double-strand breaks (DSBs) were both attenuated. Rad51 deficiency in anchorage-independence was not associated with Rad51 promoter activity, and was not compensated by a constitutive overexpression of Rad51 cDNA. Instead, Rad51 protein level and its ability to colocalize with DSBs were restored in the presence of proteosome inhibitors, or when cells from the suspension cultures were allowed reattachment. Presented results indicate that anchorage-independence sensitizes prostate cancer cells to genotoxic agents; however, it also attenuates faithful component of DNA repair by targeting stability of Rad51. This temporal attenuation of HRR may contribute to the accumulation mutations after DNA damage, and possibly the selection of new adaptations in cells, which survived genotoxic treatment.
PPARs are nuclear receptors belonging to the superfamily of steroid hormone receptors. In the cerebellum three cellular layers: molecular, Purkinje cell and granular, are all positive for PPAR-alpha ...and PPAR-gamma transcripts; however in granule neurons which undergo malignant transformation to form medulloblastoma, PPAR-alpha predominates. Recent reports indicate a potential role of lipid lowering drugs, fibrates and statins in anticancer treatment. One candidate for the tumor chemoprevention is fenofibrate. It has been widely used to lower plasma levels of triglycerides and cholesterol, and prevent development of arteriosclerosis mainly through the regulation of apolipoprotein genes expression. Fenofibrate is also a potent ligand for PPAR-alpha. Recent studies revealed its broad function as differentiation inducer, inflammatory response modulator, and potential anticancer agent. Our results indicate that very aggressive mouse medulloblastoma cell line, BsB8, which expresses JCV T-antigen, as well as human medulloblastoma cell lines, D283, D384 and D425 express high quantities of PPAR-alpha. In addition, medulloblastoma cells responded to the fenofibrate treatment by a significant upregulation of the PPARs responsive elements. The same treatment attenuated several IGF-I-induced signaling pathways including attenuation of IRS-1, Akt, and GSKSbeta phosphorylation. Importantly, we have observed that the fenofibrate treatment resulted in a severe attenuation of cell growth responses to IGF-I, evaluated by the monolayer and soft agar assays. Interestingly, growth retardation effects of fenofibrate were accompanied by a severe G1 cell cycle arrest and low level of apoptosis. In conclusion, our results show that PPAR-dependent growth inhibition by fenofibrate involves down-regulation of several IGF-I-activated signaling pathways, and suggest that supplementation with this non-toxic drug may improve effectiveness of radio and chemotherapy regiments against medulloblastoma.
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