Partitioning of cancer therapeutics in nuclear condensates.
Antineoplastic Agents
/ pharmacology
Cell Cycle Proteins
/ genetics
Cell Nucleus
/ metabolism
Chromobox Protein Homolog 5
Chromosomal Proteins, Non-Histone
/ genetics
Drug Resistance, Neoplasm
Green Fluorescent Proteins
/ genetics
Humans
Mediator Complex Subunit 1
/ genetics
Neoplasms
/ drug therapy
Nuclear Proteins
/ genetics
Nucleophosmin
Recombinant Proteins
/ genetics
Serine-Arginine Splicing Factors
/ genetics
Transcription Factors
/ genetics
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
19 06 2020
19 06 2020
Historique:
received:
09
09
2019
revised:
24
02
2020
accepted:
29
04
2020
entrez:
20
6
2020
pubmed:
20
6
2020
medline:
9
7
2020
Statut:
ppublish
Résumé
The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
Identifiants
pubmed: 32554597
pii: 368/6497/1386
doi: 10.1126/science.aaz4427
pmc: PMC7735713
mid: NIHMS1647011
doi:
Substances chimiques
Antineoplastic Agents
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
MED1 protein, human
0
Mediator Complex Subunit 1
0
Nuclear Proteins
0
Recombinant Proteins
0
Transcription Factors
0
Chromobox Protein Homolog 5
107283-02-3
Nucleophosmin
117896-08-9
SRSF2 protein, human
147153-65-9
Green Fluorescent Proteins
147336-22-9
Serine-Arginine Splicing Factors
170974-22-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1386-1392Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM123511
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117370
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007287
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007191
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM087237
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM034277
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA213333
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG002668
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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