Lysosomotropic Features and Autophagy Modulators among Medical Drugs: Evaluation of Their Role in Pathologies

Abstract

The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical medicine. Attention was primarily focused on the most promising agents acting as autophagy inducers, which offer a new window for treatment and/or prophylaxis of various diseases, including type 2 diabetes mellitus, Parkinson’s disease, and atherosclerosis. The present review summarizes current knowledge on the lysosomotropic features of medical drugs, as well as autophagy inducers, and their role in pathological processes.

Treatment with Autophagy Inducer Trehalose Alleviates Memory and Behavioral Impairments and Neuroinflammatory Brain Processes in db/db Mice

“…Aberrant autophagy plays a key role in aging, type 2 diabetes mellitus, and neurodegeneration [34]. Suppression of autophagy in db/db mice partially resembles the changes that occur in aging [35].…”

“…Sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin and dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin reactivate glomerular autophagy in db/db mice, thus manifesting a positive effect [37]. Recently, trehalose, an inducer of autophagy, was suggested as a possible positive factor in the control of neurodegeneration development and in the regulation of blood glucose levels [34,37]. Trehalose might also be used in the treatment of other diseases, such as cardiometabolic, liver, and other illnesses followed by disturbances in glucose metabolism [2,34,38].…”

“…Recently, trehalose, an inducer of autophagy, was suggested as a possible positive factor in the control of neurodegeneration development and in the regulation of blood glucose levels [34,37]. Trehalose might also be used in the treatment of other diseases, such as cardiometabolic, liver, and other illnesses followed by disturbances in glucose metabolism [2,34,38]. Trehalose restores autophagy and some neuronal deficits induced by hyperglycemia [39][40][41].…”

Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug–ADC Interaction in Cancer Chemotherapy

“…Our results suggest that the underlying mechanism of the attenuated T-DM1 cytotoxicity involves primarily the lysosomal accumulation of drugs and the subsequent inhibition of SLC46A3 function. Macrolides are weakly basic amphiphiles that accumulate in lysosomes by ion trapping under acidic conditions. , Because SLC46A3 is a lysosomal transporter involved in the escape of Lys-SMCC-DM1 to the cytoplasm and is a critical determinant of T-DM1 therapeutic efficacy in vitro and in vivo, ,, the lysosomal accumulation of compounds that inhibit SLC46A3 may interfere with T-DM1 efficacy. Our previous work showed that lysosomotropic drugs that inhibit SLC46A3, including clarithromycin and erythromycin, reduce T-DM1 efficacy .…”

Trehalose Activates Hepatic and Myocardial Autophagy and Has Anti-Inflammatory Effects in db/db Diabetic Mice

“…Some compounds (β-glucans) have been proven to reduce risk factors of cardiovascular events, thereby improving the treatment of diabetes and of its complications [ 65 ]. Recently, trehalose, a known inducer of autophagy [ 10 , 66 , 67 ], was suggested as a possible therapeutic agent for the control of neurodegeneration and for the regulation of blood glucose levels. Trehalose treatment has significantly attenuated pathological changes in the hypothalamus (by inducing autophagy in this brain region) of mice and alleviated behavioral aberrations of mice in models of neurodegeneration.…”