P-glycoprotein Mediates Drug Resistance via a Novel Mechanism Involving Lysosomal Sequestration

Yamagishi, Tetsuo; Sahni, Sumit; Sharp, Danae M.; Arvind, Akanksha; Jansson, Patric J.; Richardson, Des R.

doi:10.1074/jbc.m113.514091

Cited by 176 publications

(253 citation statements)

References 42 publications

Supporting

Mentioning

243

Contrasting

Order By: Relevance

“…One possibility is that lysosomes are involved in MP-mediated delivery of drugs into the nucleus. It is interesting to point out that normal acidic lysosomes tend to sequester chemotherapeutic drugs, leading to increasd drug resistance [37]. Dysfunction in lysosomes can result in enhanced drug sensitivity of cancer cells [38,39].…”

Section: Discussionmentioning

confidence: 99%

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

et al. 2016

View full text Add to dashboard Cite

Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications.

show abstract

Section: Discussionmentioning

confidence: 99%

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Notably, DOX is inherently fluorescent and as such does not require detection using a secondary antibody (7). Progold anti-fade DAPI was used to mount coverslips (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…1Ai), reaching their intracellular targets, e.g. the nucleus (7). Due to the ionization properties of DOX, the agent becomes trapped in this organelle as a result of its protonation at lysosomal pH (i.e.…”

Section: Multidrug Resistance (Mdr)mentioning

confidence: 99%

“…It has been demonstrated that Pgp not only functions to efflux drugs out of the cell when present on the plasma membrane but also serves a functional intracellular role in the lysosomal membrane to induce resistance (7). In this case, lysosomal membrane Pgp transports substrates into the organelle, which then acts as a "safe house" to prevent cytotoxic chemotherapeutics, such as doxorubicin (DOX; Fig.…”

Section: Multidrug Resistance (Mdr)mentioning

confidence: 99%

“…Due to the ionization properties of DOX, the agent becomes trapped in this organelle as a result of its protonation at lysosomal pH (i.e. pH 5) (7).…”

Section: Multidrug Resistance (Mdr)mentioning

confidence: 99%

See 2 more Smart Citations

Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter

Seebacher

Lane

Jansson

et al. 2016

Journal of Biological Chemistry

Self Cite

111

View full text Add to dashboard Cite

Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in multidrug-resistant tumors where a stressful micro-environment exists.

show abstract

Cancer Drug Resistance – Targets and Therapies

Zdrazil

Ecker

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

show abstract

P-glycoprotein Mediates Drug Resistance via a Novel Mechanism Involving Lysosomal Sequestration

Cited by 176 publications

References 42 publications

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter

Cancer Drug Resistance – Targets and Therapies

Contact Info

Product

Resources

About