Significance of Paraptosis in Cancer Treatment and its Induction by Natural Molecules

All organisms rely on Programmed Cell Death (PCD) to keep their cells in a constant state of homeostasis and to control their development, health, and illness. PCD is classified by its mechanisms, such as autophagy, apoptosis, paraptosis, and necrosis. Apoptosis, or PCD, is usually avoided by cancer cells due to treatment resistance. Hence, paraptosis, a newly found PCD that causes mitochondria and/or ER hypertrophy, could be a new treatment strategy. Paraptosis is characterized by proteostasis, redox and ion imbalance disruptions, vacuoles, and mitochondrial and ER dysfunction in cancer cells. Paraptosis creates cytoplasmic vacuoles from the ER, distinguishing it from autophagy and apoptosis. It does not require caspase stimulation or undergo morphological changes like apoptosis. Recently, multiple natural compounds, metallic complexes, and novel inducers have been shown to trigger paraptosis in diverse cancer cell lines, enhancing their anticancer effects. Understanding paraptosis will lay the basis for generating innovative smallmolecule cancer treatments. Since paraptosis differs from apoptosis and other PCD in morphology and biochemistry, understanding its regulators is vital. This article covers the routes, inducers, stimuli, and modulators of paraptosis, which causes cell death.