Browsing by Author "Chaves, Raquel"
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- Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2- carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studiesPublication . Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Calhelha, Ricardo C.; Lima, Raquel T.; Vasconcelos, M. Helena; Adega, Filomena; Chaves, Raquel; Queiroz, Maria João R.P.Hepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino- -(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1ae1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2ae2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI50 values on HepG2 cells of 1.2 mM compared to 2.9 mM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI50 > 125 mM against 3.3 mM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also performed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogs.
- Anti-proliferative activity of thieno[3,2-b]pyridine derivatives in tumoral and primary hepatic cell lines.Publication . Abreu, Rui M.V.; Queiroz, Maria João R.P.; Ferreira, Isabel C.F.R.; Adega, Filomena; Chaves, Raquel
- ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast CancerPublication . Santos, Sara; Batista, Claudia S.; Abreu, Rui M.V.; Bastos, Estela; Amorim, Irina; Gut, Ivo G.; Gartner, Fátima; Chaves, RaquelHuman ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.
- Motor coordination, activity, and fitness at 6 years of age relative to activity and fitness at 10 years of agePublication . Souza, Michele Caroline de; Chaves, Raquel; Lopes, Vitor P.; Malina, Robert M.; Silva, Rui Garganta; Seabra, André; Maia, José A.R.Health benefits of physical activity (PA) and physical fitness (PF) are reasonably well established, but tracking studies of PA and PF in childhood have not ordinarily considered the role of motor coordination. Objectives: To compare the growth status, gross motor coordination (GMC), PA and PF characteristics of children at 6 years of age relative to aerobic fitness (fit, unfit) and PA (active, sedentary) at 10 years. Methods: 285 primary school children (142 girls, 143 boys) resident on the four main Azorean islands, Portugal, were measured annually (in the Fall) from 6 to 10 years. ANOVA and t-tests were computed with SPSS 17.
- New potential anti-hepatocellular carcinoma (HCC) agents: in vitro evaluation of anti-HCC activity and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylates and QSAR studiesPublication . Abreu, Rui M.V.; Queiroz, Maria João R.P.; Ferreira, Isabel C.F.R.; Calhelha, Ricardo C.; Adega, Filomena; Chaves, RaquelHepatocellular carcinoma (HCC) is a major health problem with more than 660,000 new cases per year worldwide [1]. HCC is resistant to commonly used treatments like chemotherapy and radiotherapy and new anti-HCC therapies are urgently needed. Sorafenib was the first approved small molecule against HCC and underlines the importance of identifying potential new anti-HCC drugs [2]. Thirty-two 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylates, previously prepared by some of us [3,4], were evaluated as potential new anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells, generally regarded as a good HCC model, and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety on the substituent of the 6-position emerged as the key element for the anti-HCC activity.