New Visions on Natural Products and Cancer Therapy: Autophagy and Related Regulatory Pathways

Abstract

Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated ~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers.

Temozolomide, Simvastatin and Acetylshikonin Combination Induces Mitochondrial Dependent Apoptosis in GBM Cells which is Regulated by Autophagy

“…Caspase-3/-7 are the final executing caspases and induce the last steps in nuclear events related to apoptosis [38,59,60]. We measured their activity at 60 hrs to investigate the impact of Caspase activation in TMZ, Simva, ASH, TMZ/Simva, and TMZ/Simva/ASH-induced apoptosis in GBM cells.…”

“…Recently, Shikonin (SHK) [32], a highly lipophilic compound from Lithospermum erythrorhizon root that is commonly used in Chinese folklore remedies through its antiinflammatory and pleiotropic effects, has been introduced as an antitumor agent [34][35][36][37][38]. Besides the strong anticancer feature of Shikonin and its analogs, they also have the ability of circumventing cancer drug resistance [39,40].…”

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…Autophagy plays an important role in several CSC functions, including maintenance and survival [ 68 , 69 , 70 , 71 , 72 , 73 ], adaptation to the TME [ 74 , 75 , 76 ], migration and invasion [ 77 , 78 ], chemo- and immune-resistance [ 79 , 80 , 81 , 82 ], and metabolic reprogramming [ 83 , 84 , 85 ]. Numerous studies suggest that the inflammatory response in the TME is regulated by autophagy via TAMs and CAFs.…”

Ceramides and Ceramide Synthases in Cancer: Focus on Apoptosis and Autophagy

“…Apoptosis is a programmed process whereby cells are committed to death (49). There are two main apoptosic pathways namely intrinsic or extrinsic (50).…”