Autophagy Modulators in Cancer Therapy

Abstract

Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.

The Role of Autophagy in Anti-Cancer and Health Promoting Effects of Cordycepin

“…The dysregulation of autophagy is associated with many types of diseases, including cancers, neurodegenerative diseases, kidney diseases, immune dysfunction diseases, and so on [ 43 ]. In cancer biology, autophagy plays dual roles in tumor promotion and suppression, which contributes to cancer cell development and/or proliferation [ 44 ].…”

“…One study showed that a high level of autophagy occurs in RAS-activating mutated cells, and cell survival is dependent on autophagy during nutrient starvation [ 47 ]. Therefore, autophagy contributes to tumor cell survival by enhancing stress tolerance and supplying nutrients to meet the metabolic demands of tumors, and the inhibition of autophagy or knockdown of autophagy genes can result in tumor cell death [ 44 ].…”

Punicalagin in Cancer Prevention—Via Signaling Pathways Targeting

“…Although basal autophagy proceeds constitutively at a low level, it heightens with nutrient/oxygen deprivation to increase the survival odds under stressful conditions. Autophagy can be further divided into macroautophagy, selective autophagy, microautophagy, and chaperone-mediated autophagy, from which macroautophagy, the most common and best studied type, is usually referred to as simply autophagy [ 53 ]. Macroautophagy proceeds through the formation of an autophagosome (a sequestration of a fragment of cytoplasm by surrounding its contents with double membranes) and then its fusion with lysosome (yielding autophagolysosome) to deliver hydrolases required for the degradation of the enclosed molecules [ 54 ].…”

“…For example, whereas Shen et al [ 59 ] observed decreased beclin-1 expression in ovarian cancer, especially in more advanced stages, Cai et al [ 67 ] noted its overexpression correlated positively with the better survival rates. Recent literature data describing autophagy function in cancer development, as well as signal transduction pathways implicated in this process, focused on anticancer therapy (including the assessment of phytotherapeutics) have been addressed in several review papers [ 53 , 55 , 56 , 68 , 69 , 70 ].…”

“…Therefore, in some instances, it is difficult to clarify the exact machinery yielding lethal effects. Complex interrelationships occur also in the case of apoptosis and autophagy, from which both seem to employ such factors as p53, Bcl-2/Beclin, p62, or caspases (as discussed by Buzun et al [ 53 ]). In particular, p53 protein, termed “the guardian of the genome”, is implicated in various routes, except for apoptosis or autophagy, depending on the physio/pathological context, after the cell cycle arrest, it can stimulate also the processes leading to senescence [ 73 ].…”