Janaina Fernandes

Pentacyclic triterpenes from Chrysobalanaceae species: cytotoxicity on multidrug resistant and sensitive leukemia cell lines.

Plants are known as important source in the search for new anti-cancer agents. Cytotoxicity-guided fractionation of leaves and fruits from Licania tomentosa Bench and leaves from Chrysobalanus icaco L. resulted in the isolation of betulinic, oleanolic and pomolic acids. These triterpenoids inhibited the growth and induced apoptosis of K562, an erythroleukemia cell line. Most importantly, they also inhibited the proliferation of Lucena 1, a vincristine-resistant derivative of K562 that displays several multidrug resistance (MDR) characteristics. Taken together, our findings emphasize the anti-tumor activity of these triterpenes on leukemia cell lines and call attention to their potential as anti MDR agents.

Oleanolic Acid Initiates Apoptosis in Non-Small Cell Lung Cancer Cell Lines and Reduces Metastasis of a B16F10 Melanoma Model In Vivo

Background Drug resistance, a process mediated by multiple mechanisms, is a critical determinant for treating lung cancer. The aim of this study is to determine if oleanolic acid (OA), a pentacyclic triterpene present in several plants, is able to circumvent the mechanisms of drug resistance present in non-small cell lung cancer (NSCLC) cell lines and to induce their death. Principal Findings OA decreased the cell viability of the NSCLC cell lines A459 and H460 despite the presence of active, multidrug-resistant (MDR) MRP1/ABCC1 proteins and the anti-apoptotic proteins Bcl-2 and survivin. These effects are due to apoptosis, as evidenced by the capacity of OA to induce fragmentation of DNA and activate caspase 3. Induction of NSCLC cell death by OA cannot be explained by inhibition of the MDR proteins, since treatment with triterpene had little or no effect on the activity or expression of MRP1. Moreover, treatment with OA had no effect on the expression of the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic protein Bax, altering the Bcl-2/Bax balance towards a pro-apoptotic profile. OA also decreased the expression of the anti-apoptotic protein survivin. Furthermore, OA decreased the expression of the angiogenic vascular endothelial growth factor (VEGF) and decreased the development of melanoma-induced lung metastasis. Conclusion Our data provide a significant insight into the antitumoral and antimetastatic activity of OA in NSCLC and suggest that including OA in the NSCLC regimens may help to decrease the number of relapses and reduce the development of metastases.

Topological Polar Surface Area Defines Substrate Transport by Multidrug Resistance Associated Protein 1 (MRP1/ABCC1)

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a very promiscuous transporter. Herein we used topological polar surface area (TPSA), a descriptor defined as the sum of surfaces of polar atoms in a molecule, to analyze drug transport by MRP1. We suggested that compounds with high TPSA are transported while those with low TPSA are not. The conjugation to GSH increases TPSA values favoring transport. A strong correlation between TPSA and transport properties (K(m)) was also found.

Effects of oleanolic acid on pulmonary morphofunctional and biochemical variables in experimental acute lung injury

We analysed the effects of oleanolic acid (OA) on lung mechanics and histology and its possible mechanisms of action in experimental acute lung injury (ALI). BALB/c mice were randomly divided into Control (saline, ip) and ALI (paraquat, 25 mg/kg, ip) groups. At 1 h, both groups were treated with saline (SAL, 50 μl ip), OA (10 mg/kg ip), or dexamethasone (DEXA, 1 mg/kg ip). At 24 h, lung static elastance, viscoelastic pressure, and alveolar collapse reduced more after OA compared to DEXA administration. Tumour necrosis factor-α, macrophage migration inhibitory factor, interleukin-6, interferon-γ, and transforming growth factor-β mRNA expressions in lung tissue diminished similarly after OA or DEXA. Conversely, only OA avoided reactive oxygen species generation and yielded a significant decrease in nitrite concentration. OA and DEXA restored the reduced glutathione/oxidized glutathione ratio and catalase activity while increasing glutathione peroxidase induced by paraquat. In conclusion, OA improved lung morphofunction by modulating the release of inflammatory mediators and oxidative stress.

Tumor malignancy is engaged to prokaryotic homolog toolbox.

Cancer cells display high proliferation rates and survival provided by high glycolysis, chemoresistance and radioresistance, metabolic features that appear to be activated with malignancy, and seemed to have arisen as early in evolution as in unicellular/prokaryotic organisms. Based on these assumptions, we hypothesize that aggressive phenotypes found in malignant cells may be related to acquired unicellular behavior, launched within a tumor when viral and prokaryotic homologs are overexpressed performing likely robust functions. The ensemble of these expressed viral and prokaryotic close homologs in the proteome of a tumor tissue gives them advantage over normal cells. To assess the hypothesis validity, sequences of human proteins involved in apoptosis, energetic metabolism, cell mobility and adhesion, chemo- and radio-resistance were aligned to homologs present in other life forms, excluding all eukaryotes, using PSI-BLAST, with further corroboration from data available in the literature. The analysis revealed that selected sequences of proteins involved in apoptosis and tumor suppression (as p53 and pRB) scored non-significant (E-value>0.001) with prokaryotic homologs; on the other hand, human proteins involved in cellular chemo- and radio-resistance scored highly significant with prokaryotic and viral homologs (as catalase, E-value=zero). We inferred that such upregulated and/or functionally activated proteins in aggressive malignant cells represent a toolbox of modern human homologs evolved from a similar key set that have granted survival of ancient prokaryotes against extremely harsh environments. According to what has been discussed along this analysis, high mutation rates usually hit hotspots in important conserved protein domains, allowing uncontrolled expansion of more resistant, death-evading malignant clones. That is the case of point mutations in key viral proteins affording viruses escape to chemotherapy, and human homologs of such retroviral proteins (as Ras, Akt and EGFR) can elicit the same phenotype. Furthermore, a corollary to this hypothesis presumes that target-directed anti-cancer therapy should target human protein domains of low similarity to prokaryotic homologs for a well-succeeded anti-cancer therapy.

Chemical composition of the volatile fractions from wild and in vitro plants of Anemia tomentosa var. anthriscifolia (Pteridophyta)

Anemia tomentosa var. anthriscifolia is a very aromatic fern with ornamental potential. The major constituent of the volatile fraction of this plant is the triquinane sesquiterpene (-)-9-epi-presilphiperfolan-1-ol, which displays in vitro antibacterial activity against Mycobacterium tuberculosis. In order to investigate the chemical composition of this volatile fraction in relation to their triquinane sesquiterpenes upon in vitro multiplication, the tissue culture of this plant was established. Gametophytes and early sporophytes were successfully developed from spores inoculated in MS medium without growth regulators. Volatiles of both in vitro and wild plants were extracted by simultaneous distillation and extraction (SDE) and analyzed by gas chromatography/flame ionization detector (GC/FID) and GC–mass spectrometry (GC/MS). Twenty-seven constituents were evidenced in the volatiles of the wild plant, accounting for 93.4% of its total composition, whereas only seven constituents accounted for 97.0% of the total composition of the volatiles of the in vitro plants, respectively. The volatiles from the in vitro plants were composed mainly of monoterpenes (79%), whereas those of the wild plants comprised mostly sesquiterpenes (97.5%). The major constituents from in vitro plants are α-pinene (20.7%), trans-pinocarveol (31.0%) and pinocarvone (27.3%), whereas the major constituents from wild plants are silphiperfol-6-ene (11.7%), 9-epi-presilphiperfolan-1-ol (31.3%) and presilphiperfolan-8-ol (21.2%).

The study of homology between tumor progression genes and members of retroviridae as a tool to predict target-directed therapy failure

Oncogenes are the primary candidates for target-directed therapy, given that they are involved directly in the progression and resistance of tumors. However, the appearance of point mutations can hinder the treatment of patients with these new molecules, raising costs and the need to development new analogs that target the novel mutations. Based on an analysis of homologies, the present study discusses the possibility of predicting the failure of a protein as a pharmacological target, due to its similarities with retrovirus sequences, which have extremely high mutation rates. This analysis was based on the molecular evidence available in the literature, and widely-used and well-established PSI-BLAST, with two iterations and maximum of 500 aligned sequences. The possibility of predicting which newly-discovered genes involved in tumor progression would likely result in the failure of targeted therapy, using free, simple and automated bioinformatics tools, could provide substantial savings in the time and financial resources needed for long-term drug development.