2024-03-29T01:57:21Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/110092024-01-24T20:04:56Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
00925njm 22002777a 4500
dc
Cash, Timothy P
author
Alcalá, Sonia
author
Rico-Ferreira, María Del Rosario
author
Hernández-Encinas, Elena
author
García, Jennifer
author
Albarrán, María Isabel
author
Valle, Sandra
author
Serrano, Manuel
author
Sainz, Bruno
author
Blanco-Aparicio, Carmen
author
Pastor Fernandez, Joaquin
author
Martinez, Sonia
author
Munoz, Javier
author
2020-07-04
Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
Cancers (Basel) . 2020;12(7):1790
2072-6694
http://hdl.handle.net/20.500.12105/11009
32635473
10.3390/cancers12071790
Cancers
DEATH
PATHWAY
DISRUPTION
METABOLISM
SIRAMESINE
INHIBITORS
SURVIVAL
Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells.