Дисертації з теми "Cancer cachexia, metabolism, pyruvate"

The findings reported in this thesis hihlight the pivotal role of a metabolic change towards fermentation in the induction of cancer cachexia in myotubes treated with the conditioned medium of CT26 murine colon carcinoma cell line. Particularly, cachectic myotubes manifest a reduced oxygen consumption, increased lactate production and several mitochondrial alterations including a decreased activity of PDH. Our results reveal that PDH activity restoration, achieved by glycolysis or lactic fermentation inhibition was able to prevent cancer cachexia induction and previously observed metabolic alterations. This could be due to an increased availability of pyruvate within mitochondria. In agreement, pyruvate supplementation was able to prevent cancer cachexia induction and previously observed metabolic alterations, triggering a PDH activity restoration. Thus, pyruvate supplementation could represent a new tool to counteract cancer cachexia induction and development.

Cancer cachexia is characterized by weight loss and insulin resistance. Previous work has shown blunted protein anabolism in insulin resistant conditions. This study tested whether hyperaminoacidemia with hyperinsulinemia elicits blunted whole-body protein anabolism in cachectic non-small cell lung cancer (NSCLC). Whole-body [13C]leucine and [3H]glucose kinetics were assessed in 8 NSCLC patients and 10 age and weight-matched controls during a euglycemic, hyperinsulinemic, clamp with isoaminoacidemia (Iso-AA), followed by hyperaminoacidemia (Hyper-AA). Glucose utilization increased from Iso-AA to Hyper-AA but was lower in NSCLC patients. During Iso-AA, protein breakdown decreased and synthesis was unchanged resulting in positive net balance that was lower in NSCLC patients. During Hyper-AA, synthesis increased but breakdown was unchanged resulting in increased net balance in both groups. In summary, weight-losing NSCLC patients demonstrate insulin resistance of whole-body glucose and protein metabolism. Physiologic hyperaminoacidemia normalized their anabolic response to that of controls and did not impair insulin sensitivity of glucose.
La perte de poids et la résistance à l'insuline caractérisent la cachexie due au cancer. Un anabolisme protéique amoindri a été démontré dans des conditions d'insulino-résistance. Cette étude a évalué si l'hyperaminoacidemie et l'hyperinsulinemie résultent en un défaut de l'anabolisme protéique corporel dans la cachexie due au cancer du poumon « non à petites cellules » (NSCLC). La cinétique des protéines ([13C]leucine) et du [3H]glucose corporels ont été évalués chez 8 patients avec NSCLC et 10 hommes en santé, d'âge et de poids similaires, à l'aide du clamp hyperinsulinique, euglycémique, isoaminoacidémique (Iso-AA), suivi d'une hyperaminoacidémie (Hyper-AA). L'utilisation du glucose a augmenté entre Iso-AA et Hyper-AA, mais il était plus bas chez les patients NSCLC. Pendant Iso-AA, la dégradation des protéines a diminué et la synthèse n'a pas changé, résultant en une balance positive moindre chez les NSCLC. En Hyper-AA, la synthèse a augmenté, mais la dégradation n'a pas changé, ce qui a augmenté davantage la balance positive, dans les deux groupes. En résumé, les patients NSCLC perdant du poids ont démontré une résistance du métabolisme glucidique et protéique à l'insuline. L'hyperaminoacidémie a normalisé leur réponse anabolique à celle des contrôles sans affecter la sensibilité du glucose à l'insuline.

Prostate cancer is the second most diagnosed and cause of cancer-related death in Australian men. Resistance to treatment and non-specificity of the drugs is a major bottleneck for prostate cancer. Recently, nano-formulated drugs are being developed for targeted drug delivery into the cancer cells. Prostate cancer cells use aerobic glycolysis promoted by the pyruvate dehydrogenase kinase-1 (PDK1) gene for energy production. We targeted PDK1 using nano-formulations selective for prostate cancer cells and tested these using in vitro and in vivo models. Nano-conjugated Radicicol was identified as most promising drug and potential useful co-therapy agent with inhibitory effect on tumour development.

Monitoring the early responses of tumours to treatment is a crucial element in guiding therapy and increasing patient survival. To achieve this, we are using magnetic resonance imaging (MRI), which can provide detailed physiological information with relatively high temporal and spatial resolution. In combination with the dynamic nuclear polarisation (DNP) technique, high signal-to-noise is obtained, resulting in a powerful tool for in vivo 13C metabolic imaging. However, detection of hyperpolarised substrates is limited to a few seconds due to the exponential decay of the polarisation with the longitudinal relaxation time constant T1. This work aimed to improve the combination of hyperpolarisation and metabolic NMR/ MRI by extending the observation timescale of the technique. Working with quantum mechanical properties of the detected substrates, long lifetimes might be accessible by using the nuclear singlet configuration of two coupled nuclei. The singlet state is immune to intramolecular dipole-dipole relaxation processes, which is one of the main sources of signal decay in MRI. In favourable situations, the singlet relaxation time constant can be much longer than T1, so transfer of the polarisation into the singlet state may allow one to extend the usable time period of the nuclear hyperpolarisation. Here we studied the relaxation of hyperpolarised metabolites, including those found in the TCA cycle, and examined the possibility of extending their observation timescale by storing the polarisation in the long-lived singlet state. The polarisation remains in this state until it is eventually required for imaging. We also investigate how one may track polarised metabolites after injection into a subject due to the transfer of polarisation to the solvent by Overhauser cross-relaxation, so that the 13C polarisation remains untouched until imaging is required. In this way we should be able to interrogate slower metabolic processes than have been examined hitherto using hyperpolarised 13C MRS, and better understand metabolic changes induced in tumours by treatment.

The loss of muscle mass leading to cachexia is rarely identified in early lung cancer. Fasting blood and muscle biopsy were collected in 59 non-small cell lung cancer (NSCLC) and 16 non-cancer patients, at the beginning of thoracic surgery. Serum C-reactive protein (CRP), and IL-6 were higher in NSCLC. In weight-losing NSCLC, food intake and serum albumin were lower, CRP, and TNF-alpha were higher. Although the expression of genes of the ubiquitin-proteasome system was not different, ubiquitinated-protein levels were lower and negatively correlated with ph-FOX01 in weight-losing patients. This would suggest lower muscle proteolytic rates in the early stages of NSCLC. Ph-FOXO1 also related to the degree of weight loss and stage of NSCLC. These data suggest that in early stages of the disease, weight and muscle loss could be mainly due to reduced food intake, rather than accelerated proteolysis, which reinforces the potential for successful dietary interventions to prevent or delay the onset of cachexia.

BACKGROUND: Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. RESULTS: Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized 13C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors. CONCLUSIONS: Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.

La cachexie affecte environ la moitié des patients atteints d’un cancer et est caractérisée par une perte progressive de la masse corporelle résultant principalement d’une perte de masse musculaire squelettique. Cette perte de masse musculaire squelettique associée à une perte de force musculaire contribue fortement à réduire la qualité de vie des patients, l’efficacité des traitements et à terme, la survie des patients. Plusieurs facteurs sont connus pour être impliqués dans la régulation de la masse musculaire. Parmi eux, les glucocorticoïdes sont des hormones stéroïdiennes sécrétées sous le contrôle de l’axe hypothalamo-hypophysaire qui sont connues pour induire l’atrophie musculaire mais aussi pour avoir une action systémique via l’activation ou l’expression de gènes dans plusieurs tissus. Nous faisons l’hypothèse que la voie des glucocorticoïdes pourrait être activée pendant la cachexie associée au cancer dans les souris ApcMin/+, un model murin de cancer intestinal. Nous rapportons ici que l’activation du catabolisme musculaire était associée à une reprogrammation complète du métabolisme du foie. En outre, nous montrons une activation de l’axe hypothalamo-hypophysaire associée à une augmentation du niveau en corticostérone (le glucocorticoïde principal chez les rongeurs) dans le sérum, le muscle quadriceps et le foie des souris à un stade avancé de la cachexie associée au cancer. La signature transcriptionnelle dans le muscle quadriceps et le foie des souris à un stade avancé de la cachexie associée au cancer reflète celle observée dans des souris traitées avec de la dexaméthasone, un analogue des glucocorticoïdes. Il est important de souligner que l’inhibition de la cachexie associée au cancer par l’inactivation du gène de la myostatine dans les souris ApcMin/+ a restauré les niveaux en corticostérone et abolit la reprogrammation génique dans le muscle squelettique et le foie. Ensemble, ces données indiquent que les glucocorticoïdes induisent un programme transcriptionnel pour réguler de façon coordonnée la perte de masse musculaire et le remaniement du métabolisme hépatique. L’inhibition de cette réponse par l’invalidation du gène de la myostatine souligne l’existence d’un dialogue moléculaire entre le muscle squelettique et le foie
Cachexia affects about half of cancer patients and is characterized by a progressive body mass loss mainly resulting from skeletal muscle depletion. This loss of skeletal muscle mass together with a decrease in muscle force strongly contribute to reduce cancer patient quality of life, treatment efficiency and ultimately patient survival. Many factors are known to be involved in the regulation of skeletal muscle homeostasis. Among them, glucocorticoids are steroid hormones secreted under the control of the hypothalamic-pituitary axis that have been well described to promote skeletal muscle atrophy but also to exert systemic actions through activation or repression of gene expression in many tissues. We hypothesized that the glucocorticoid pathway could be activated during cancer cachexia in ApcMin/+ mice, a mouse model of intestinal cancer. Here, we reported that activation of skeletal muscle catabolism was associated with a complete reprogramming of liver metabolism. Moreover, we showed an activation of the hypothalamus-pituitary axis that was associated with an increase in the level of corticosterone (the main glucocorticoid in rodent) in serum, quadriceps muscle and liver of advanced cancer cachectic mice. The transcriptional signature in quadriceps muscle and liver of advanced cancer cachectic mice significantly mirrored that observed in mice treated with dexamethasone, an analog glucocorticoid. Importantly, the inhibition of cancer cachexia by myostatin gene invalidation in ApcMin/+ mice restored corticosterone levels and abolished skeletal muscle and liver gene reprogramming. Together, these data indicate that glucocorticoids drive a transcriptional program to coordinately regulate skeletal muscle mass loss and hepatic metabolism rewiring. The inhibition of this response by myostatin gene invalidation highlights the existence of a molecular dialog between skeletal muscle and liver

Metabolic deregulation is an emergent hallmark of prostate cancer and studies show that altered patterns of metabolic pathways involved in the development of malignancy. A large genetic association on microRNA (miRNA) related genetic variations recently identified single nucleotide polymorphisms (SNPs) in two key metabolic genes. This thesis analysed the role of metabolic genes and functional validation of SNPs and associated miRNAs involved in the regulation of these genes as a mediator of prostate cancer aetiology. The findings from this study suggest that studies of miRNAs and their interactions with SNPs could provide valuable insights into the complicated mechanisms of prostate cancer risk and identify suitable molecular pathways for targeted therapy.

Whilst progress has been made in reducing mortality in some cancers, mortality rates remain high in many cancers and there is a need to develop novel therapeutic strategies. In this thesis, various pharmacological strategies designed to enhance the activity of existing therapeutic drugs were evaluated. Cancer cells are dependent upon aerobic glycolysis (the Warburg effect) and glutamine uptake. Using clinically approved tyrosine kinase inhibitors and Bortezomib, significant enhancement of chemosensitivity was observed when used in combination with inhibitors of lactate dehydrogenase (Gossypol) and pyruvate kinase dehydrogenase (Dichloroacetate). In contrast, depletion of glutamine from media had to be extensive in order to induce cell death and cell death only occurred after prolonged exposure to glutamine-deprived conditions. This suggests that glutamine depletion strategies alone are unlikely to be successful but may be useful in combination with other agents targeting glutamine addiction in cancer cells. Finally, Temozolomide (TMZ) is an important drug in the treatment of glioblastomas but its activity is reduced by resistance mechanisms including O6 methyl guanine methyltransferase (MGMT) and mismatch repair (MMR). This thesis has identified analogues of TMZ (EA02-45, EA02-59, EA02-64 and EA02-65) that are MGMT and MMR independent in terms of inducing cell kill in vitro. These compounds are promising leads for future development. In conclusion, this thesis has demonstrated that interfering with the metabolic phenotype of cancer can enhance the activity of existing drugs and identified novel analogues of TMZ that circumvent drug resistance mechanisms that hamper the efficacy of TMZ.

Orientador: Maria Cristina Cintra Gomes Marcondes
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O câncer pode promover a morte do hospedeiro, pois durante sua evolução há modificações da homeostasia dos processos metabólicos, promovendo profundas alterações caracterizadas como caquexia, que por sua vez relaciona-se à diminuição da qualidade e do tempo de vida do hospedeiro. Assim, no presente estudo, analisamos os efeitos da evolução do crescimento de neoplasia - carcinossarcoma de Walker 256 - em ratos jovens e adultos e os efeitos modulatórios do tratamento desses animais com EPA (ácido eicosapentaenóico) sobre o processo de caquexia e a concentração de citocinas anti e proinflamatórias no músculo gastrocnêmio, pois o tecido muscular é o tecido mais afetado no processo de caquexia. Foram utilizados 108 ratos Wistar machos, com idade de 30 dias (jovens) e 100 dias (adultos), os quais foram distribuídos de acordo com o local de implante tumoral, intraperitônio e subcutâneo, e tratamento ou não com ácido eicosapentaenóico, 100?g/Kg de peso corpóreo. Os animais receberam gavagem diária do EPA (animais tratados) ou de óleo mineral (grupos sem tratamento) até a fase pré-agônica. A partir dos órgãos coletados, foram calculados o ganho de peso corpóreo, os pesos relativos de cada órgão, do tumor e da carcaça. Com o objetivo de identificarmos a via de degradação protéica predominante nos grupos experimentais, foram avaliados, no tecido muscular, o teor de proteína muscular total e as atividades das seguintes enzimas: chymotrypsin-like, catepsinas B e H, calpaína e fosfatase alcalina,. A partir do sangue desses animais foram feitas análises fluorimétricas do fator de crescimento semelhante à insulina (IGF) e das citocinas - interleucinas 4 (IL-4), 6 (IL-6) e 10 (IL-10), interferon gama (INF-?) e leptina, utilizando-se kits específicos para citômetro de fluxo de fluorescência (Luminex). Também foi analisada a expressão gênica, no tecido muscular, por reação em cadeia da polimerase em tempo real (PCR-RT), para a via proteossômica e também para os fatores eucarióticos de inicialização. Os dados indicam efeitos modulatórios do EPA sobre o tecido muscular (manutenção da proteína e do peso), principalmente para os grupos jovens, e também no processo inflamatório crônico (aumento de citocinas pró e antiinflamatórias). Entretanto, efeitos mais expressivos do EPA não foram verificados na prevenção da espoliação de gordura (gordura perirrenal e leptina), no processo de síntese protéica (manutenção da expressão gênica de fatores eucarióticos de inicialização) ou também sobre a via proteossômica
Abstract: Cancer can promotes the host death, because during its evolution there are modifications in metabolic processes of homeostasis, promoting deep changes characterized as cachexia, which in turn relates with reduction in quality and lifetime of the host. Thus, in this study, we analyze the effects of development in Walker 256 carcinoma evolution - in young and adults rats and the modulatory effect of treatment with EPA (eicosapentaenoic acid) in gastrocnemius muscle as this tissue is the most affected in the cachexia process. Wistar males rats were used (n=108 animals), 30 days-old (young) and 100 days-old (adults), which were distributed according to the tumour implant, intraperitoneally and subcutaneously and treatment or not with eicosapentaenoic acid, 100 ?g/Kg of body weight. The animals receive daily EPA by gavage (treated animals) or nujol (sham groups) and were cared up to pre-agonic state. The bodies weight were measured and the body weight gain was calculated, as well the relative weights of tissues, tumour, and carcass. In order to identify the predominant pathway of protein degradation the total muscle protein content and proteolytic enzymes activities (chymotrypsin-like, cathepsin B and H, calpain and alkaline phosphatase) were measured in gastrocnemius muscle. The blood samples were assessed to measure the insulin-like growth factor 1 (IGF-1), leptin and the cytokines - interleukins (IL-4), 6 (IL-6) and 10 (IL-10), gamma interferon (INF-?), using specific kits for cytometer fluorescence (Luminex). It was also examined gene expression, in the muscle tissue, by real-time polymerase chain reaction (RT-PCR), assessing keys of ubiquitin-proteasome pathway and also on the eukaryotic initiation factors. The data indicated some modulatory effects of EPA on the muscle tissue (maintenance of protein and weight), mainly for the young rats, and also the chronic inflammatory process. However, more expressive effects of EPA have not been verified as preventing fat wasting (perirenal fat and leptin), nor in the process of protein synthesis (maintenance of eukaryotic initiating factors gene expression) or also in the ubiquitin-proteasome via
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular

The Warburg effect occurs in 90% of tumors, where glycolysis is favored despite the presence of oxygen. The activity of pyruvate dehydrogenase kinases (PDKs) is increased in cancer cells, suppressing glucose oxidation. Inhibition of PDKs can redirect glucose flux into the mitochondria, reversing the Warburg effect. Dichloroacetate (DCA) is a relatively non-toxic PDK inhibitor that inhibits all four isoforms of PDK with differing potency. We examined the determinants of DCA sensitivity, the ability of DCA to enhance apoptosis, and how DCA regulates cell metabolism. We found in a range of cancer types, that all four PDK isoforms can be expressed and contribute to tumor metabolism. DCA inhibited cancer cell growth in vivo and in vitro, activated PDH and reduced lactate production. The magnitude of DCA growth inhibition correlated with the PDK expression profiles of the cells, with PDK3 (highest Ki for DCA) conferring low sensitivity towards DCA. PDK2 siRNA-knockdown inhibited growth to a similar extent to DCA, whilst PDK3 knockdown significantly increased sensitivity to DCA, confirming sensitivity to DCA is determined by PDK expression. Further examination of PDKs in patient samples will increase the likelihood of DCA being successfully translated into clinical use, with the PDK expression profile being a biomarker for sensitivity to DCA. The mechanisms by which DCA can sensitize cancer cells towards apoptosis were investigated, as we observed that DCA increased hypoxia-induced apoptosis. DCA enhanced the effects of 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO; a novel anti-mitochondrial agent) in vitro. DCA increased ROS levels, which were fully responsible for enhancing PENAO apoptosis in MDA-MB-231 cells, but only partially in T-47D cells. The two cell lines were metabolically distinct, potentially explaining the different mechanisms by which DCA enhanced apoptosis. PDK knockdown experiments revealed that DCA could enhance apoptosis via off-target effects. The pro-apoptotic proteins Noxa and Puma were investigated, however DCA did not alter their expression. DCA however depolarized the mitochondrial membrane potential in T-47D cells, suggesting that this is an additional mechanism of DCA apoptosis enhancement in these cells. Nevertheless, DCA sensitized all cancer cell lines tested towards apoptosis. Thus DCA has potential to be used in combination with other cytotoxic agents in order to reduce their adverse effects. To understand the mechanism of action, the metabolic effects of DCA on cancer cells were investigated. Gas chromatography-mass spectrometry metabolomics revealed a general trend of increase in the proportion of anabolic metabolites upon DCA treatment. Furthermore, long-term DCA treatment resulted in DCA-resistance, which was accompanied by correlating changes in the PDK expression profile. These findings thus open avenues of further exploration on the mechanism of DCA action and resistance factors. Our findings provide potential biomarkers for sensitivity to DCA, and evidence that DCA can be combined with other therapies for enhanced anti-cancer effects. We have opened future directions of identifying DCA-resistance factors. This will allow using drugs in combination with DCA that specifically target these resistance factors. Collectively our work will allow DCA to have greater success in clinical trials by being able to target patients most likely to respond.

Cachexia is the leading cause of morbidity and mortality in patients with cancer. Mechanisms The effects of cancer cachexia and chemotherapy on small intestinal protein metabolism and the mechanisms regulating recovery are currently not known. Compromises to small intestinal protein metabolism may impair normal digestive and immune functions within the intestine and may negatively impact the whole body. Colon 26 adenocarcinoma induces cancer cachexia in mice, characteristic to the human condition, and this tumour can be cured with 100% efficacy using the experimental alkylating agent, cystemustine. In the present study, both healthy mice and colon 26 adenocarcinoma bearing mice were given either a single i.p. injection of N-(2- Chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N-nitrosourea (cystemustine)(20 mg/kg) or saline 3 d following the onset of cachexia in colon 26 adenocarcinoma bearing mice. The rate of protein synthesis was determined in vivo using the flooding dose method. The possible involvement of proteolysis was assessed through northern blot hybridization of mRNA encoding components of the major proteolytic systems (lysosomal, calcium dependent, ATP-ubiquitin dependent). Villus and crypt morphology was studied through histological analysis. In tumour bearing mice not treated with chemotherapy, cancer cachexia reduced the rate of protein synthesis in the small intestine relative to healthy mice on a fractional (-15 to -20%, P0.05). In treated mice, acute cytotoxicity of chemotherapy did not promote further wasting of small intestinal protein mass, nor did it result in damage to intestinal morphology. In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P<0.05) was evident in healthy mice treated with cystemustine, suggesting that the small intestine in cachectic mice responds differently to chemotherapy than in normal healthy mice. Complete and rapid recovery of small intestinal protein mass in cured mice resulted from an increase in the rate of protein synthesis compared to healthy mice on a fractional (+25%, P<0.05) and absolute basis (+35%, P<0.05); northern blot hybridization suggested no involvement of proteolysis during recovery.

Dynamic nuclear polarization and dissolution of 13C-labeled metabolite allows dynamic imaging of metabolism in-vivo. However, the spatial and temporal resolutions of magnetic resonance spectroscopic imaging are limited by the duration of free-induction decay acquisitions and the T1-based, non-recoverable polarization decay. This thesis describes the implementation of a spectral-spatial radiofrequency excitation pulse with a `flyback' echo-planar readout trajectory to dynamically image [1-13C]-pyruvate and [1-13C]-lactate in an interleaved manner. This technique excites a single resonance of either [1-13C]-pyruvate or [1-13C]-lactate and generates dynamic images with 5mm in-plane resolution. Metabolite dynamics extracted from the images and the corresponding non-localized spectroscopic data reveal similar kinetic rates upon fitting to a kinetic model. This demonstrates the feasibility of probing metabolism in heterogeneous tissues in-vivo with dynamic interleaved 13C MR imaging.

碩士
國立臺灣海洋大學
食品科學系
98
Abstract Cachexia, occurs in terminal cancer patients refers to a state of severe malnutrition characterized by anorexia, the loss of adipose tissue and skeletal muscle mass. Eicosapentaenoic acid (EPA) has been shown to attenuate the enhanced protein degradation. Furthermore, Red Yeast Rice also has been reported to inhibit tumor promotion. This study examines the synergic effects of Prophyra dentate (EPA rich) combined with Monascus purpureus supplementation in mice bearing the cachexia-inducing CT26 colon adenocarcinoma. P. dentate and M. purpureus (PM) diet were given by oral ad lib administration of feed chow to BALB/c mice, after multiple Cisplatin (CP) i.p. injection (3 mg/kg body weight) . Mice were divided into ten groups by different dosages, each group have ten mice and treatment lasted for 21 days. The mice were then sacrificed and analysis. In our result, Cisplatin created more serious cachexia symdrome. The PM diet at high dose can inhibit NF-B activated and IL-6 secrete so that can attenuate muscle wasting and weight loss. PM diet at five dose can also decrease liver and kidney’s toxicity by Cisplatin. In 28 days feeding subacute toxicity study, the 100 fold dosage PM diet didn’t have any toxicity with hamster. But it may had function of anti-obesity and regulation the blood lipid. Furthermore, Porphyra-Monascus fermentation powder extract is better than Monascus purpureus powder extract at anti-oxidation ability, anti-tumor ability and anti-inflammation ability. In conclusion, Animal models are useful in the study of cachexia. PM diet might have anti-cachexia/cancer propeties and it’s in safety. In addition, Porphyra-Monascus fermentation powder might have more useful propeties to attenuate cancer cachxia. Keywords: cancer cachexia, Monascus purpureus, Prophyra dentate