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.