| Title | Partitioning of cancer therapeutics in nuclear condensates. |
| Publication Type | Journal Article |
| Year of Publication | 2020 |
| Authors | Klein IA, Boija A, Afeyan LK, Hawken SWilson, Fan M, Dall'Agnese A, Oksuz O, Henninger JE, Shrinivas K, Sabari BR, Sagi I, Clark VE, Platt JM, Kar M, McCall PM, Zamudio AV, Manteiga JC, Coffey EL, Li CH, Hannett NM, Guo YEric, Decker T-M, Lee TIhn, Zhang T, Weng J-K, Taatjes DJ, Chakraborty A, Sharp PA, Chang YTae, Hyman AA, Gray NS, Young RA |
| Journal | Science |
| Volume | 368 |
| Issue | 6497 |
| Pagination | 1386-1392 |
| Date Published | 2020 Jun 19 |
| ISSN | 1095-9203 |
| Keywords | Antineoplastic Agents, Bromodomain Containing Proteins, Cell Cycle Proteins, Cell Nucleus, Chromobox Protein Homolog 5, Chromosomal Proteins, Non-Histone, Drug Resistance, Neoplasm, Green Fluorescent Proteins, Humans, Mediator Complex Subunit 1, Neoplasms, Nuclear Proteins, Nucleophosmin, Recombinant Proteins, Serine-Arginine Splicing Factors, Transcription Factors |
| Abstract | 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. |
| DOI | 10.1126/science.aaz4427 |
| Alternate Journal | Science |
| PubMed ID | 32554597 |
| PubMed Central ID | PMC7735713 |
| Grant List | R01 GM123511 / GM / NIGMS NIH HHS / United States R01 GM117370 / GM / NIGMS NIH HHS / United States T32 GM007287 / GM / NIGMS NIH HHS / United States T32 DK007191 / DK / NIDDK NIH HHS / United States P01 CA155258 / CA / NCI NIH HHS / United States T32 GM087237 / GM / NIGMS NIH HHS / United States R01 GM034277 / GM / NIGMS NIH HHS / United States U01 CA213333 / CA / NCI NIH HHS / United States R01 HG002668 / HG / NHGRI NIH HHS / United States |
