Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition

• Published in: International journal of molecular sciences Vol. 21; no. 12; p. 4392
• Main Authors: Hraběta, Jan, Belhajová, Marie, Šubrtová, Hana, Merlos Rodrigo, Miguel Angel, Heger, Zbyněk, Eckschlager, Tomáš
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.06.2020; MDPI
• Subjects: Acidification; Active transport; Adenosine triphosphatase; Angiogenesis; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Brain cancer; Breast cancer; Cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Chemoresistance; chemoresistance of cancer cells; Chloroquine; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; DNA; Drug dosages; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drugs; Enzymes; Exocytosis; Gene Expression Regulation, Neoplastic - drug effects; H+-transporting ATPase; Humans; Hydrogen-Ion Concentration; Hydrophobicity; Hypoxia; Kinases; lysosomal sequestration; Lysosomes; Lysosomes - drug effects; Lysosomes - enzymology; lysosomotropic agents; Metabolism; Metabolites; metallothioneins; Metastasis; Neoplasms - drug therapy; Neoplasms - enzymology; Phosphorylation; Protein-tyrosine kinase; Proteins; Review; Transcription factors; Trapping; Tyrosine; V-ATPase; V-ATPase inhibitors; Vacuolar Proton-Translocating ATPases - antagonists & inhibitors; lysosomal sequestration; V-ATPase; metallothioneins; chemoresistance of cancer cells; V-ATPase inhibitors; lysosomotropic agents
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21124392

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.