Fatty acid synthase as a potential new therapeutic target for cervical cancer.

Fatty acid synthase (FASN) is the rate-limiting enzyme for the de novo synthesis of fatty acids in the cytoplasm of tumour cells. Many tumour cells express high levels of FASN, and its expression is associated with a poorer prognosis. Cervical cancer is a major public health problem, representing the fourth most common cancer affecting women worldwide. To date, only a few in silico studies have correlated FASN expression with cervical cancer. This study aimed to investigate in vitro FASN expression in premalignant lesions and cervical cancer samples and the effects of a FASN inhibitor on cervical cancer cells. FASN expression was observed in all cervical cancer samples with increased expression at more advanced cervical cancer stages. The FASN inhibitor (orlistat) reduced the in vitro cell viability of cervical cancer cells (C-33A, ME-180, HeLa and SiHa) in a time-dependent manner and triggered apoptosis. FASN inhibitor also led to cell cycle arrest and autophagy. FASN may be a potential therapeutic target for cervical cancer, and medicinal chemists, pharmaceutical researchers and formulators should consider this finding in the development of new treatment approaches for this cancer type.

Synthesis and antileukemic activity of an ursolic acid derivative: A potential co-drug in combination with imatinib.

Imatinib, a specific Bcr-Abl tyrosine kinase inhibitor, is the most commonly used drug in the treatment of chronic myeloid leukemia. However, optimal response is not achieved in up to 33% of patients. Therefore, development of novel therapeutic strategies for chronic myeloid leukemia is critical. Betulinic (1) and ursolic (2) acids are natural pentacyclic triterpenes that exhibit antileukemic activities. In this study, we evaluated the effects of pharmacomodulations at the C-3 position of the triterpene moiety of betulinic and ursolic acids on their activity against K562 leukemia cells. Six new derivatives (1a-2c) were synthesized and evaluated for pro-apoptotic and anti-proliferative effects in mammalian and leukemic cells. 2c derivative containing an amine group at the C-3 position of ursolic acid was the most active against leukemia cells with an IC50 value of 5.2 µM after 48 h of treatment. 2c did not exhibit cytotoxic effects against VERO and HepG2 cells and human lymphocytes, showing a good selectivity index for cancer over normal cells. Induced cell death by apoptosis via caspases 3 and 8, and also caused cell cycle arrest as evidenced by accumulation of cells in the G1 phase and decreased cell population in the G2 phase. Furthermore, co-treatment of 2c with imatinib, the chemotherapy drug most commonly used to treat leukemia, resulted in a synergistic effect. Our findings provide a strong rationale for further investigation of combination therapy using the 2c derivative and imatinib in pre-clinical studies.

Betulinic Acid and Brosimine B Hybrid Derivatives as Potential Agents against Female Cancers.

BACKGROUND: Cancer is a multifactorial disease, representing one of the leading causes of death worldwide. On a global estimate, breast cancer is the most frequently occurring cancer in women and cervical cancer, the fourth most common. Both types of cancer remain the major cause of cancer-related mortality in developing countries. A strategy for rational drug design is hybridization, which aims to bring together in one molecule, two or more pharmacophores in order to reach several biological targets. OBJECTIVE: The objective of this work was to develop new hybrids based on natural pharmacophores: Betulinic acid (1) and brosimine b (2), active in female cancer cell lines. METHODS: The coupling reactions were carried out by Steglich esterification. Different compounds were designed for the complete and simplified structural hybridization of molecules. The anticancer activities of the compounds were evaluated in human cervical adenocarcinoma (HeLa), human cervical metastatic epidermoid carcinoma (ME-180), and human breast adenocarcinoma (MCF-7) cell lines. RESULTS: Hybrid 3 presented higher potency (IC50 = 9.2 ± 0.5µM) and SI (43.5) selectively in MCF-7 cells (in relation to Vero cells) with its cytotoxic effect occurring via apoptosis. In addition, compound 6 showed activity in MCF-7 and HeLa cells with intermediate potency, but with high efficacy, acting via apoptosis as well. CONCLUSION: In this context, we showed that the combination of two complex structures generated the development of hybrids with differing inhibitory profiles and apoptotic modes of action, thus representing potential alternatives in female cancer treatment.

Hepcidin is a useful biomarker to evaluate hyperferritinemia associated with metabolic syndrome.

Investigation of hyperferritinemia in metabolic syndrome patients represents a diagnostic challenge, but it is essential for the identification of individuals with iron overload. Hepcidin negatively regulates iron absorption and release. An increase in hepcidin occurs when iron levels are sufficient or in inflammatory states, conditions often associated with hyperferritinemia. Hemochromatosis causes hyperferritinemia due to iron overload, but frequently has low hepcidin levels. Our aim was to evaluate biochemical and molecular parameters related to iron metabolism in patients with metabolic syndrome. We evaluated 94 patients with metabolic syndrome according to the International Diabetes Federation criteria in a cross-sectional study. Anthropometric data and diagnostic criteria for metabolic syndrome, iron dosage, ferritin, transferrin saturation, hepcidin, and the C282Y and H63D mutations in the HFE hemochromatosis gene were evaluated. Prevalence of hyperferritinemia in the study population was 27.7% and was higher in males (46.2%) than in females (14.5%). Increase in transferrin saturation correlated with mutations in the hemochromatosis gene. Hyperferritinemia was associated to transferrin saturation and hepcidin after logistic regression analysis. In conclusion, hyperferritinemia is a frequent finding in metabolic syndrome patients, most frequently in men; and hepcidin assessment can be useful for the investigation of ferritin increase in those subjects.

Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia.

BACKGROUND: Chronic myeloid leukemia (CML) is currently treated with imatinib, a Bcr-Abl inhibitor. However, resistance to this drug usually develops over time. Triptolide, a diterpenoid triepoxide, has been shown active against CML cells resistant to imatinib, acting mainly on the level of Bcr-Abl transcription inhibition. OBJECTIVE: Here, we used the triterpene betulinic acid, a known proteasome inhibitor with potential antileukemic activity, as a scaffold for the generation of analogues with predicted triptolide biological activity. METHOD: Betulinic acid derivatives were designed based on the structure-activity relationship of triptolide and evaluated for their cytotoxic effects in CML cells, lymphocytes and human keratinocytes (HaCaT), as well as against the proteasome complex. The main modification performed on betulinic acid was fluorination at C-28 and epoxidation, both of which are responsible for enhancing activity of triptolide. A total of 10 compounds were obtained: 6 previously described and 4 novel compounds. The cytotoxic activity over a CML cell line (K562) was assessed using flow cytometry and compared to lymphocytes and HaCaT. RESULT: The results show that betulinic acid was the most cytotoxic compound against CML cells, showing a good selectivity index for cancer over normal cells. The most important trend for the activity in betulinic acid derivatives is the presence of a free hydroxyl group at C-3 and a carboxyl group at C-28. Results also indicated that the epoxide is important for enhancing the activity, while modification at C-28 worsens the activity. CONCLUSION: Proteasome inhibition assays suggest that proteasome is the main target for betulinic acid and its derivatives.

Diagnóstico laboratorial das leucemias mielóides agudas / Laboratory diagnosis of acute myeloid leukemias

As leucemias agudas caracterizam-se pela proliferação clonal e pelo bloqueio maturativo das células hematopoéticas, com substituição difusa da medula óssea por células neoplásicas. A leucemia mielóide aguda (LMA) é um grupo heterogêneo de doenças clonais do tecido hematopoético, que acomete predominantemente idosos acima de 60 anos de idade. A LMA apresenta oito subtipos distintos morfologicamente: LMA M0 a M7. Os métodos diagnósticos para identificação da LMA e classificação dos subtipos são baseados em critérios morfológicos, citoquímicos e de imunofenotipagem, acrescidos de análise genética. Além de ser importante para a diferenciação do tipo da linhagem da leucemia, se mielóide (LMA) ou linfóide (LLA), o diagnóstico é também de grande importância para identificar a leucemia bifenotípica aguda (BAL). O objetivo deste trabalho foi realizar uma revisão bibliográfica sobre LMA, dando ênfase aos métodos laboratoriais utilizados para a sua identificação e diferenciação.

Ontogenetic study of the effects of energetic nutrients on amino acid metabolism of rat cerebral cortex.

We studied the effect of various energetic nutrients on metabolism of L-[U-14C]leucine and [1-14C]glycine in cerebral cortex of rats at different ages. At gestational age, glucose and lactate stimulated protein synthesis from L-[U-14C]leucine and [1-14C]glycine and from L-[U-14C]leucine, respectively; glucose, beta-OH-butyrate and lactate stimulated lipid synthesis from L-[U-14C]leucine. At 10 days of age, glucose, mannose, and fructose stimulated protein synthesis, and glucose and mannose stimulated oxidation to CO2 as well as lipid synthesis from L-[U-14C]leucine. In adult rats, glucose, mannose, and fructose stimulated protein synthesis from L-[U-14C]leucine and [1-14C]glycine; glutamine also markedly decreased the oxidation of L-[U-14C]leucine and [1-14C]glycine in 10-day-old and adult rats.