Oral lipid nanocomplex of BRD4 PROteolysis TArgeting Chimera and vemurafenib for drug-resistant malignant melanoma.

Autor: Saraswat A; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Vartak R; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Hegazy R; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA; Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt., Fu Y; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Rao TJR; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Billack B; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Patel K; College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: patelk2@stjohns.edu.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Dec; Vol. 168, pp. 115754. Date of Electronic Publication: 2023 Oct 21.
DOI: 10.1016/j.biopha.2023.115754
Abstrakt: BRAF inhibitors (BRAFi) like vemurafenib (VEM) provide initial regression in mutated melanoma but rapidly develop resistance. Molecular pathways responsible for development of resistance against VEM finally converge towards the activation of oncogenic c-Myc. We identified an epigenetic approach to inhibit the c-Myc expression and resensitize BRAFi-resistant melanoma cells. ARV-825 (ARV) was employed as a BRD4 targeted PROteolysis TArgeting Chimera that selectively degrades the BRD4 to downregulate c-Myc. ARV synergistically enhanced the cytotoxicity of VEM in vitro to overcome its resistance in melanoma. Development of ARV and VEM-loaded lipid nanocomplex (NANOVB) significantly improved their physicochemical properties for oral delivery. Most importantly, oral administration of NANOVB substantially inhibited tumor growth at rate of 41.07 mm 3 /day in nude athymic mice. NANOVB treatment resulted in prolonged survival with 50% of mice surviving until the experimental endpoint. Histopathological analysis revealed significant tumor necrosis and downregulation of Ki-67 and BRD4 protein in vivo. Promising in vivo antitumor activity and prolonged survival demonstrated by NANOVB signifies its clinical translational potential for BRAFi-resistant melanoma.
Competing Interests: Declaration of Competing Interest All authors have no competing interest to declare.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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