Biology subjects

Pereira, D. M.

Publications and source records attributed to Pereira, D. M..

3 recordsLinked to original sources

bioRxiv2023

Structural modification of naturally-occurring phenolics as a strategy for developing cytotoxic molecules towards cancer cells

Natural products belonging to different chemical classes have been established as a promising source of novel anticancer drugs. Several low molecular weight compounds from the classes of monoterpenes, phenylpropanoids and flavonoids were shown to possess anticancer activities in previous studies. In this work, over 20 semisynthetic derivatives of molecules belonging to these classes, namely thymol, eugenol and 6-hydroxyflavanone were synthesized and tested for their cytotoxicity against two human cancer cell lines, namely gastric adenocarcinoma (AGS cells) and human lung carcinoma (A549 cells). An initial screening based on viability assessment was performed in order to identify the most cytotoxic compounds at 100 M. The results evidenced that two 6-hydroxyflavanone derivatives were the most cytotoxic among the compounds tested, being selected for further studies. Noteworthy, in a general way some of the derivatives synthesized displayed enhanced toxicity when compared with their natural counterparts. Moreover, LDH assay showed that the loss of cell viability was not accompanied by a loss of membrane integrity, thus ruling out a necrotic process. Morphological studies with AGS cells demonstrated chromatin condensation compatible with apoptosis, confirmed by the activation of caspase 3/7. Furthermore, a viability assay on non-cancer human embryonic lung fibroblast cell line (MRC-5) confirmed these two derivatives possess selective anticancer activity.

pharmacology and toxicology↗

bioRxiv2022

A survey of naturally-occurring molecules as new endoplasmic reticulum stress activators with selective anticancer activity

The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road towards desirable success rates of cancer treatments is still long and paved with uncertainty. With this work, we aim to select natural products that act via endoplasmic reticulum (ER) stress, since the latter is known to be a vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Starting from a chemical library of over 90 natural products, nontoxic molecules towards non-cancer cells were selected to be assessed for their toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. The active molecules towards at least one of these cell lines were studied in a battery of ensuing assays designed to show the involvement of ER stress in the observed cytotoxic effect, for instance, by evaluating ER stress-related gene expression or caspase activation. We show that several natural products are selectively cytotoxic against malignant cell lines, with their cytotoxicity relying on ER stress and activation of the unfolded protein response (UPR). Berberine and emodin are proposed as potential leads for the development of more potent ER stressors to be used as selective anticancer agents. Berberine was effective against the two cell models we worked with, disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation, standing out as the most promising candidate to aid in the development of novel ER stress-based strategies against neoplastic disease.

pharmacology and toxicology↗

bioRxiv2022

A pipeline for natural small molecule inhibitors of endoplasmic reticulum stress

The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while also being the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterize the pathogenesis of neurodegenerative disease. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The effect of the compounds on calcium homeostasis, key gene and protein expression, and levels of protein aggregation were evaluated in fibroblasts, and subsequently in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it, among which delphinidin stands out as the most promising candidate against neurodegeneration.

pharmacology and toxicology↗