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Non-small cell lung cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)-phosphoethanolamine (PEG-PE), we obtain Fluplatin@PEG-PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.

Titel:	Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer.
Autor/in / Beteiligte Person:	Bi, YY ; Chen, Q ; Yang, MY ; Xing, L ; Jiang, HL
Link:	View record at Springer (Volltext)
Zeitschrift:	Nature communications, Jg. 15 (2024-03-29), Heft 1, S. 2759
Veröffentlichung:	[London] : Nature Pub. Group, 2024
Medientyp:	academicJournal
ISSN:	2041-1723 (electronic)
DOI:	10.1038/s41467-024-47080-3
Schlagwort:	Humans Cisplatin pharmacology Cisplatin therapeutic use Tumor Suppressor Protein p53 genetics Tumor Suppressor Protein p53 metabolism Drug Resistance, Neoplasm genetics Fluvastatin therapeutic use Neoplasm Recurrence, Local drug therapy Neoplasm Recurrence, Local genetics Cell Line, Tumor Mutation Carcinoma, Non-Small-Cell Lung drug therapy Carcinoma, Non-Small-Cell Lung genetics Carcinoma, Non-Small-Cell Lung pathology Lung Neoplasms drug therapy Lung Neoplasms genetics Lung Neoplasms pathology Nanoparticles Antineoplastic Agents pharmacology Antineoplastic Agents therapeutic use Phosphatidylethanolamines Polyethylene Glycols
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nat Commun] 2024 Mar 29; Vol. 15 (1), pp. 2759. <i>Date of Electronic Publication: </i>2024 Mar 29. MeSH Terms: Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Nanoparticles* ; Antineoplastic Agents* / pharmacology ; Antineoplastic Agents* / therapeutic use ; Phosphatidylethanolamines* ; Polyethylene Glycols* ; Humans ; Cisplatin / pharmacology ; Cisplatin / therapeutic use ; Tumor Suppressor Protein p53 / genetics ; Tumor Suppressor Protein p53 / metabolism ; Drug Resistance, Neoplasm / genetics ; Fluvastatin / therapeutic use ; Neoplasm Recurrence, Local / drug therapy ; Neoplasm Recurrence, Local / genetics ; Cell Line, Tumor ; Mutation References: Nat Cell Biol. 2016 Nov;18(11):1233-1243. (PMID: 27775703) ; Cell. 2010 Apr 2;141(1):39-51. (PMID: 20371344) ; Nature. 2021 Jul;595(7868):585-590. (PMID: 34163070) ; J Clin Oncol. 2021 May 10;39(14):1584-1594. (PMID: 33449813) ; Science. 2020 Oct 9;370(6513):. (PMID: 33004676) ; J Transl Med. 2017 Oct 31;15(1):221. (PMID: 29089030) ; Nat Rev Cancer. 2007 Aug;7(8):573-84. (PMID: 17625587) ; Circulation. 2020 Jan 28;141(4):285-300. (PMID: 31707831) ; Nat Biomed Eng. 2021 Sep;5(9):1048-1058. (PMID: 34045730) ; Signal Transduct Target Ther. 2021 Jul 12;6(1):263. (PMID: 34248142) ; Cell. 2021 Feb 18;184(4):1081-1097.e19. (PMID: 33606978) ; J Thorac Oncol. 2016 Jun;11(6):850-61. (PMID: 26899019) ; Clin Cancer Res. 2014 Apr 15;20(8):2104-14. (PMID: 24429878) ; Nat Med. 2019 Oct;25(10):1601-1606. (PMID: 31591592) ; Nat Med. 2021 Aug;27(8):1345-1356. (PMID: 34385702) ; Chem Soc Rev. 2022 Apr 4;51(7):2544-2582. (PMID: 35262108) ; Drug Resist Updat. 2020 Mar;49:100671. (PMID: 31841768) ; Cancer Lett. 2011 Dec 22;312(2):209-18. (PMID: 21937165) ; Ann Oncol. 2007 Sep;18(9):1500-5. (PMID: 17698835) ; J Clin Oncol. 2012 May 10;30(14):1692-8. (PMID: 22473169) ; Genome Res. 2018 Nov;28(11):1747-1756. (PMID: 30341162) ; Int J Mol Sci. 2021 Jul 27;22(15):. (PMID: 34360768) ; J Control Release. 2012 Jun 28;160(3):637-51. (PMID: 22405904) ; Nat Rev Drug Discov. 2023 Feb;22(2):127-144. (PMID: 36216888) ; J Clin Oncol. 2016 Nov 20;34(33):4000-4007. (PMID: 27646943) ; CA Cancer J Clin. 2022 Jan;72(1):7-33. (PMID: 35020204) ; Nature. 2022 Aug;608(7924):795-802. (PMID: 35978189) ; Nat Metab. 2020 Feb;2(2):132-141. (PMID: 32694690) ; J Clin Oncol. 2010 Feb 10;28(5):761-6. (PMID: 20048189) ; Nat Rev Cancer. 2014 Nov;14(11):709-21. (PMID: 25342630) ; Cancer Discov. 2019 Jul;9(7):962-979. (PMID: 31068365) ; Nat Rev Clin Oncol. 2021 Sep;18(9):547-557. (PMID: 33911215) ; Nature. 2018 Jan 24;553(7689):446-454. (PMID: 29364287) ; Sci Rep. 2019 Nov 28;9(1):17747. (PMID: 31780674) ; Nat Protoc. 2022 Sep;17(9):2108-2128. (PMID: 35859135) ; Chem Soc Rev. 2020 Nov 21;49(22):8113-8136. (PMID: 32597908) ; Clin Cancer Res. 2021 Mar 1;27(5):1526-1537. (PMID: 33203642) ; Cell. 2014 Apr 10;157(2):382-394. (PMID: 24725405) ; Cancer Discov. 2012 May;2(5):401-4. (PMID: 22588877) ; NPJ Precis Oncol. 2022 Sep 9;6(1):64. (PMID: 36085319) ; Ann Oncol. 2006 May;17 Suppl 5:v64-7. (PMID: 16807466) ; Nature. 1999 Jun 24;399(6738):806-9. (PMID: 10391249) ; Ann Oncol. 2019 May;30(5):863-870. (PMID: 31987360) ; Cancer Discov. 2014 Apr;4(4):405-14. (PMID: 24658082) ; Nat Cell Biol. 2018 Jan;20(1):28-35. (PMID: 29255172) ; Cancer Discov. 2023 Jan 9;13(1):56-69. (PMID: 36197521) ; Lancet Oncol. 2007 Aug;8(8):674. (PMID: 17726780) ; Cancer Cell. 2021 Apr 12;39(4):494-508.e5. (PMID: 33545063) ; Sci Signal. 2013 Apr 02;6(269):pl1. (PMID: 23550210) ; J Control Release. 2021 Mar 10;331:460-471. (PMID: 33545218) ; Nat Rev Cancer. 2021 Jan;21(1):37-50. (PMID: 33128031) ; Nat Cell Biol. 2022 Jul;24(7):1099-1113. (PMID: 35798843) ; Lancet Oncol. 2021 Nov;22(11):e501-e516. (PMID: 34735819) Grant Information: 82020108029 National Natural Science Foundation of China (National Science Foundation of China); 82073398 National Natural Science Foundation of China (National Science Foundation of China) Substance Nomenclature: Q20Q21Q62J (Cisplatin) ; 133906-05-5 (dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine) ; 0 (Tumor Suppressor Protein p53) ; 4L066368AS (Fluvastatin) ; 0 (Antineoplastic Agents) ; 0 (Phosphatidylethanolamines) ; 3WJQ0SDW1A (Polyethylene Glycols) Entry Date(s): Date Created: 20240330 Date Completed: 20240401 Latest Revision: 20240426 Update Code: 20240426 PubMed Central ID: PMC10980692

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Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer.