Destination ‘Lysosome’: a target organelle for tumour cell killing?

Abstract

Lysosomes and lysosome-related organelles constitute a system of acid compartments that interconnect the inside of the cell with the extracellular environment via endocytosis, phagocytosis and exocytosis. In recent decades it has been recognized that lysosomes are not just wastebaskets for disposal of unused cellular constituents, but that they are involved in several cellular processes such as post-translational maturation of proteins, degradation of receptors and extracellular release of active enzymes. By complementing the autophagic process, lysosomes actively contribute to the maintenance of cellular homeostasis. Proteolysis by lysosomal cathepsins has been shown to mediate the death signal of cytotoxic drugs and cytokines, as well as the activation of pro-survival factors. Secreted lysosomal cathepsins have been shown to degrade protein components of the extracellular matrix, thus contributing actively to its re-modelling in physiological and pathological processes. The malfunction of lysosomes can, therefore, impact on cell behaviour and fate. Here we review the role of lysosomal hydrolases in several aspects of the malignant phenotype including loss of cell growth control, altered regulation of cell death, acquisition of chemoresistance and of metastatic potential. Based on these observations, the lysosome is proposed as a potential target organelle for the chemotherapy of tumours. We will also present some recent data concerning the technologies for delivering chemotherapeutic drugs to the endosomal-lysosomal compartment and the strategies to improve their efficacy.

Biocompatibility, endocytosis, and intracellular trafficking of mesoporous silica and polystyrene nanoparticles in ovarian cancer cells: effects of size and surface charge groups

“…23,42 Size is particularly critical for intracellular traff icking and the f inal destination of endocytosed nanoparticles, given that endocytic compartments range between 300 nm and 1000 nm. 5 Both the 1000 nm and 50 nm amine-modified polystyrene nanoparticles were toxic to ovarian cancer cells, while 10 nm and 50 nm mesoporous silica and 30 nm carboxyl-modified polystyrene nanoparticles exerted no toxic effects on metabolism in ovarian cancer cells, consistent with previous reports showing the biotolerability of mesoporous silica 19,30,37,43 and carboxylated polystyrene 27,29,44 nanoparticles in other cell types. The potentially deleterious effects of nanoparticles on cell metabolism depend on their physicochemical characteristics, uptake efficiency, and final intracellular destination, as well as their accumulation in critical compartments.…”

“…5 To see whether the mesoporous silica and polystyrene nanoparticles converged into the same intracellular compartments after internalization, we coincubated ovarian cancer cells with these nanoparticles and followed their intracellular traffic and localization at increasing chase times. The cells were exposed to the nanoparticles at saturating conditions (30 µg/mL mesoporous silica and 75 µg/mL polystyrene, 15 minutes of incubation).…”

“…1 The high mortality rate in patients with ovarian cancer is primarily attributable to late diagnosis, when metastases have already formed, and to development of chemoresistant clones that eventually cause relapse. 2 In addition to an intrinsic inability to activate a cell death program, 3,4 mechanisms of chemoresistance in cancer cells include lysosomal sequestration and inactivation, 5 and enhanced efflux of the toxic drug. 6,7 Given the silent nature of the development of ovarian cancer and its extreme lethality, there is an urgent need to develop sensitive methods for early diagnosis of primary and secondary lesions and novel strategies to deliver cytotoxic drugs to chemoresistant clones.…”

Labeling and exocytosis of secretory compartments in RBL mastocytes by polystyrene and mesoporous silica nanoparticles

“…41 RBL mastocytes have been shown to possess two distinct subpopulations of secretory lysosome-like compartments. 22,23 It is not yet known whether these compartments interconnect the endocytic pathway, and if so, how.…”

Choosing Targets for Gene Therapy

“…Dysfunction of lysosomal hydrolases leads to loss of cell growth control and results in chemotherapy resistance as well as high metastatic potential (Castino et al 2003). Furthermore, lysosome and lysosome-related organelles are associated with Lysosomal Storage Disease (LSD), Alzheimer's disease and development of several types of tumors.…”