A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity

• Type: Article in International Scientific Journal
• Date: 2023

Authors

da Silva, DC (Author) Other; Patricia Valentao (Author) FFUP; David M Pereira (Author) FFUP

Journal

Title: Cancers

Vol. 390

Final page: 293

ISSN: 2072-6694

Publisher: MDPI

Indexing

ISI Web of Knowledge - 0 Citations

Other information

Authenticus ID: P-00X-PD1

DOI: 10.3390/cancers15010293

Abstract (EN): Simple Summary Cancer is the second cause of death worldwide, representing a massive burden on modern society. It is, therefore, urgent to increase the success rates of cancer treatments. With this work, we aim to characterize selectively cytotoxic natural products that act by inducing stress upon the endoplasmic reticulum (ER) of cancer cells. The ER is in charge of the synthesis and folding of most of the cellular proteome. ER stress is a known vulnerability of cancer cells due to their aberrant protein synthesis rates. We identified several natural products that induce selective cytotoxicity on cancer cell lines and act upon the ER. Berberine was the most promising molecule, disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation on AGS and A549 cells. Our results indicate that berberine and emodin are potential leads for the development of new pharmacological strategies against cancer. The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17