Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

Zhai, Xingjian; Hiani, Yassine El

doi:10.3390/cancers12123669

Cited by 10 publications

(7 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most chemotherapeutics used in the clinic are lipophilic, weak-base drugs that can readily be sequestered in the acidic lysosomal compartment. Once in lysosomes, these unprotonated amine-containing compounds are rapidly protonated and remain trapped in these organelles, diminishing their cytotoxic effect (Zhai and El Hiani, 2020). The lysosomotropic nature of several drugs that are widely used in the clinic because of their superior bioavailability and pharmacokinetic parameters poses a major hurdle for cancer treatment.…”

Section: Chemoresistance and Cancer Evasion Through Lysosomal Pathwaysmentioning

confidence: 99%

“…Tumor cells expressing MDR transporters effectively efflux lysosomotropic ionizable drugs that diffuse into the cytosol or are sequestered in lysosomes. Examples of hydrophobic, weak-base chemotherapeutics that are both Pgp substrates and lysosomotropic are doxorubicin, daunorubicin, vinblastine, sunitinib, vincristine, cisplatin, and sorafenib (Yamagishi et al, 2013;Colombo et al, 2014;Zhitomirsky and Assaraf, 2016;Geisslinger et al, 2020;Zhai and El Hiani, 2020). Treatment of tumor cells with these compounds induces expansion of the lysosomal system, thereby enhancing their lysosomal sequestration and drug resistance (Groth-Pedersen et al, 2007;Zhitomirsky and Assaraf, 2015;Zhao et al, 2020).…”

Section: Chemoresistance and Cancer Evasion Through Lysosomal Pathwaysmentioning

confidence: 99%

See 1 more Smart Citation

Lysosomes and Cancer Progression: A Malignant Liaison

Machado

Annunziata

Vlekkert

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

During primary tumorigenesis isolated cancer cells may undergo genetic or epigenetic changes that render them responsive to additional intrinsic or extrinsic cues, so that they enter a transitional state and eventually acquire an aggressive, metastatic phenotype. Among these changes is the alteration of the cell metabolic/catabolic machinery that creates the most permissive conditions for invasion, dissemination, and survival. The lysosomal system has emerged as a crucial player in this malignant transformation, making this system a potential therapeutic target in cancer. By virtue of their ubiquitous distribution in mammalian cells, their multifaced activities that control catabolic and anabolic processes, and their interplay with other organelles and the plasma membrane (PM), lysosomes function as platforms for inter- and intracellular communication. This is due to their capacity to adapt and sense nutrient availability, to spatially segregate specific functions depending on their position, to fuse with other compartments and with the PM, and to engage in membrane contact sites (MCS) with other organelles. Here we review the latest advances in our understanding of the role of the lysosomal system in cancer progression. We focus on how changes in lysosomal nutrient sensing, as well as lysosomal positioning, exocytosis, and fusion perturb the communication between tumor cells themselves and between tumor cells and their microenvironment. Finally, we describe the potential impact of MCS between lysosomes and other organelles in propelling cancer growth and spread.

show abstract

Section: Chemoresistance and Cancer Evasion Through Lysosomal Pathwaysmentioning

confidence: 99%

Section: Chemoresistance and Cancer Evasion Through Lysosomal Pathwaysmentioning

confidence: 99%

Lysosomes and Cancer Progression: A Malignant Liaison

Machado

Annunziata

Vlekkert

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…[62] In addition, in leukocytes, vacuoles are also reported upon exposure to various chemicals. [63,64] Indeed, many drugs used for oncologic treatment are weak bases that can be protonated and sequestered within lysosomes, thereby causing their vacuolation [65] and exerting chemoresistance in cancer cells. [66] Therefore, cytosolic vacuolation can be exploited for different purposes, including diagnosis.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Label‐Free Intracellular Multi‐Specificity in Yeast Cells by Phase‐Contrast Tomographic Flow Cytometry

Bianco,

D'Agostino,

Pirone

et al. 2023

Small Methods

View full text Add to dashboard Cite

In‐flow phase‐contrast tomography provides a 3D refractive index of label‐free cells in cytometry systems. Its major limitation, as with any quantitative phase imaging approach, is the lack of specificity compared to fluorescence microscopy, thus restraining its huge potentialities in single‐cell analysis and diagnostics. Remarkable results in introducing specificity are obtained through artificial intelligence (AI), but only for adherent cells. However, accessing the 3D fluorescence ground truth and obtaining accurate voxel‐level co‐registration of image pairs for AI training is not viable for high‐throughput cytometry. The recent statistical inference approach is a significant step forward for label‐free specificity but remains limited to cells’ nuclei. Here, a generalized computational strategy based on a self‐consistent statistical inference to achieve intracellular multi‐specificity is shown. Various subcellular compartments (i.e., nuclei, cytoplasmic vacuoles, the peri‐vacuolar membrane area, cytoplasm, vacuole‐nucleus contact site) can be identified and characterized quantitatively at different phases of the cells life cycle by using yeast cells as a biological model. Moreover, for the first time, virtual reality is introduced for handling the information content of multi‐specificity in single cells. Full fruition is proofed for exploring and interacting with 3D quantitative biophysical parameters of the identified compartments on demand, thus opening the route to a metaverse for 3D microscopy.

show abstract

“…On the other hand, lysosomes have a drug-sequestering function that diminish the availability of the drugs within cells including CDDP (Galluzzi et al, 2014; Geisslinger et al, 2020; Zhai & el Hiani, 2020; Zhitomirsky & Assaraf, 2016). Thus, the process of chemotherapy resistance may be driven by the sequestration of CDDP within lysosomes, leading to lysosomal dysfunction in A2780cis cells during the early stages of resistance acquisition (Fig.…”

Section: Discussionmentioning

confidence: 99%

Chemo-sEVs release in cisplatin-resistance ovarian cancer cells are regulated by the lysosomal function

Cerda-Troncoso

Grunenwald

Arias‐Muñoz

et al. 2023

Preprint

View full text Add to dashboard Cite

Ovarian cancer (OvCa) is an aggressive disease usually treated with cisplatin (CDDP)-based therapy. However, among the different types of cancers treated with CDDP, OvCa commonly develops chemoresistance to this treatment. The small extracellular vesicles (sEVs) play a central role in chemoresistance. In response to chemotherapy, resistant cells secrete sEVs named chemo-sEVs characterized by specific cargo landscape content involved in the transfer of chemoresistance to recipient cells. sEVs encompass a variety of vesicle types, including exosomes, and are formed as intraluminal vesicles (ILVs) within multivesicular endosomes (MVEs). MVEs follow at least two trafficking pathways regulated by RAB GTPase family members; 1) a secretory pathway where MVEs fuse with the plasma membrane (PM) for sEVs secretion, where RAB27A is the most studied; 2) a degradative pathway where MVEs fuse with lysosomes, an event controlled by RAB7. There is growing evidence suggesting that a loss of lysosomal function can increase sEVs secretion; however, whether sEVs secretion and the transfer of CDDP chemoresistance in OvCa is the result of a fine regulation between these two MVEs trafficking pathways is unknown. In this work, we study the status of these two pathways, between CDDP-sensitive (A2780) and CDDP-resistant (A2780cis) OvCa cells. We found A2780cis cells have an increased number of MVEs and ILVs structures, together with higher levels of ESCRTs machinery components and RAB27A, compared to A2780 cells. Moreover, CDDP promotes the secretion of chemo-sEVs in A2780cis cells. Interestingly, chemo-sEVs contain a high number of proteins related to DNA damage response. In addition, we determine A2780cis cells have a poor lysosomal function with reduced levels of RAB7. Surprisingly, silencing of RAB27A in A2780cis cells was found to be sufficient to restore lysosomal function and levels of RAB7 in A2780cis cells, switching into an A2780-like cellular phenotype. Next, we found rapamycin, a potent enhancer of lysosomal function, reduced the secretion of chemo-sEVs. Taken together, these results indicate that the secretion of chemo-sEVs in OvCa cells is determined by the balance between secretory MVEs and MVEs that are destined for lysosomal degradation. Thus, our results suggest that adjusting this balance between these two MVEs trafficking pathways could be a promising strategy for overcoming CDDP chemoresistance in OvCa.

show abstract

Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

Cited by 10 publications

References 132 publications

Lysosomes and Cancer Progression: A Malignant Liaison

Lysosomes and Cancer Progression: A Malignant Liaison

Label‐Free Intracellular Multi‐Specificity in Yeast Cells by Phase‐Contrast Tomographic Flow Cytometry

Chemo-sEVs release in cisplatin-resistance ovarian cancer cells are regulated by the lysosomal function

Contact Info

Product

Resources

About