Abstract
A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.
Highlights
Melanoma is a malignant tumor formed from the melanocyte’s transformation, with an estimated 106,110 new cases to be diagnosed and 7180 people expected to die due to melanoma in 2021 [1]
ARV-825 was obtained from ChemieTek (Indianapolis, IN, USA), Ni and Vemurafenib was purchased from LC Laboratories (Woburn, MA, USA), 1,2-Dioleoyl-sn-glycero-3 phosphocholine (DOPC) was purchased from Cordenpharma (Liestal, Switzerland), Plating efficiency (PE)
To investigate whether TGF-β1 production is more in the vemurafenib-resistant melanoma cells than BRAFV600E mutated melanoma cell lines, two BRAFV600E mutated melanoma cell lines A375 and SK-MEL-28 and their vemurafenib-resistant cells lines were used in enzyme linked immunosorbent assay (ELISA) assay to compare the amount of TGF-β1 release from the same number of cells
Summary
Melanoma is a malignant tumor formed from the melanocyte’s transformation, with an estimated 106,110 new cases to be diagnosed and 7180 people expected to die due to melanoma in 2021 [1]. Vemurafenib and dabrafenib were approved by the FDA as BRAF inhibitors in 2012. The MEK inhibitor was introduced to be combined with the BRAF inhibitor, which doubles the time to progression due to reactivation of mitogen-activated protein kinase (MAPK) downstream pathway. Cross resistance to MEK inhibitor was found in cell lines that acquired BRAF resistance, which limits the longterm survival of patients that harbor BRAF mutations [6,7,8]. Considering the limitations of response as well as resistance problems in the current malignant melanoma treatment, novel therapeutic treatment is encouraged to be investigated; especially combining drugs with different mechanisms
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