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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Neoplastic diseases are a leading cause of death globally, with cancer treatment success rates still limited.
• Malignant cells possess vulnerabilities, including endoplasmic reticulum (ER) stress, which can be exploited for targeted therapies.

Purpose of the Study:

• To identify natural products that induce ER stress and exhibit selective toxicity against cancer cell lines.
• To investigate the mechanisms underlying the cytotoxic effects of these natural products, focusing on ER stress and the unfolded protein response (UPR).

Main Methods:

• Screening of an in-house chemical library for molecules selectively toxic to cancer cells (AGS and A549) but not non-cancer cells.
• Assessing the involvement of ER stress and UPR in the cytotoxic effects of active compounds.
• Evaluating the impact of lead compounds on calcium (Ca2+) homeostasis, UPR gene expression, and ER-resident caspase-4 activation.

Main Results:

• Several natural products demonstrated selective cytotoxicity against cancer cell lines, primarily through ER stress induction.
• Berberine emerged as a highly promising compound, showing activity against both gastric and lung adenocarcinoma cell lines.
• Berberine was found to disrupt Ca2+ homeostasis, induce UPR target gene expression, and activate ER-resident caspase-4.

Conclusions:

• Natural products can be effective ER stress inducers with selective anticancer properties.
• Berberine and emodin show significant potential as lead compounds for developing novel, selective anticancer agents that leverage ER stress pathways.