The Switch between Protective and Nonprotective Autophagy; Implications for Autophagy Inhibition as a Therapeutic Strategy in Cancer

Abstract

Autophagy, a process of cellular self-degradation and cell survival whereby the cell generates energy and metabolic intermediates under conditions of stress (i.e., nutrient deprivation), is also commonly induced in tumor cells in response to chemotherapy and radiation. While chemotherapy-induced autophagy and radiation-induced autophagy are generally considered to have cytoprotective functions, thereby reducing tumor cell sensitivity (and potentially conferring resistance) to various treatment modalities, autophagy can also be nonprotective; furthermore, the nature of the autophagy can be altered via the "autophagic switch" depending on such factors as the p53 status of the tumor cells. Defective or compromised autophagy has also been associated with neurodegenerative diseases, raising concerns as to the impact of autophagy inhibition on normal tissue function. Furthermore, the impact of autophagy inhibition on the immune system response to therapy as well as the influence of autophagy inhibition in combination with chemotherapy or radiation on critical tissue sites such as the bone marrow remain uncertain. These are factors requiring serious consideration within the context of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy in cancer.

Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect

“…It is important to note that there are some parameters to be considered for the application of autophagy modulators in cancer treatment. For instance, the circulating concentration of pharmacological autophagy modulators, the effect and drug toxicity of autophagy modulators in normal tissues, the influence on immune antitumour response and the plausibility of autophagy switch from cytoprotective to nonprotective function [ 139 , 140 ]. Several factors have been suggested to play a role in autophagy switch including the presence of functional p53, vitamin D treatment, drug sensitivity and different stages of cancer [ 141 ].…”

FV-429 induces autophagy blockage and lysosome-dependent cell death of T-cell malignancies via lysosomal dysregulation

“…However, one point needs to be emphasized: autophagy inhibition is not always beneficial for chemotherapy treatment. For one thing, therapy-induced autophagy can also be cytotoxic 63 ; for another thing, inhibition of non-protective autophagy produces barely discernible influence on the therapeutic response 63 – 65 . At present, the mechanism of autophagy regulation in tumors is still not clear 4 .…”

STL1, a New AKT Inhibitor, Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line

“…This crosstalk between autophagy and apoptosis is facilitated by intermediates common to pathways leading to either one of the two processes and by the existence of variable cellular thresholds that can influence the cellular decision to tend for autophagy or apoptosis [ 31 ]. Another important piece of information comes from Gewirtz’s works [ 32 , 33 ], who defined four different forms of autophagy: Protective (or cytoprotective), cytotoxic, cytostatic, non-protective. Limiting the discussion to cancer cells, extensive data indicate that protective autophagy represents the cells’ “defensive” response to anticancer drugs.…”