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Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma
- Source :
- Mol Pharm
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAF(i)) and histone deacetylase inhibitors (HDAC(i)) to enhance the delivery of MC1R-targeted radiolabeled peptide ([(212)Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAF(V600E) cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [(212)Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAF(i) and/or HDAC(i) was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAF(i) and HDAC(i) significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAF(V600E) and BRAF(WT) cells. Combining [(212)Pb]DOTA-MC1L with BRAF(i) and/or HDAC(i) improved the tumor response by increasing the delivery of (212)Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDAC(i) and BRAF(i) could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.
- Subjects :
- Skin Neoplasms
Cell
Pharmaceutical Science
Pilot Projects
02 engineering and technology
030226 pharmacology & pharmacy
Drug Delivery Systems
0302 clinical medicine
Oximes
Drug Discovery
Melanoma
medicine.diagnostic_test
Imidazoles
Lead Radioisotopes
Alpha Particles
021001 nanoscience & nanotechnology
Microphthalmia-associated transcription factor
Combined Modality Therapy
Phenylbutyrates
Tumor Burden
Up-Regulation
medicine.anatomical_structure
Molecular Medicine
Female
0210 nano-technology
Receptor, Melanocortin, Type 1
Proto-Oncogene Proteins B-raf
Single Photon Emission Computed Tomography Computed Tomography
Mice, Nude
Real-Time Polymerase Chain Reaction
Article
Flow cytometry
03 medical and health sciences
Downregulation and upregulation
Cell Line, Tumor
medicine
Animals
Humans
Protein Kinase Inhibitors
neoplasms
Microphthalmia-Associated Transcription Factor
business.industry
medicine.disease
Xenograft Model Antitumor Assays
Histone Deacetylase Inhibitors
Radionuclide therapy
Cancer research
Histone deacetylase
business
Melanocortin 1 receptor
Subjects
Details
- ISSN :
- 15438392 and 15438384
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmaceutics
- Accession number :
- edsair.doi.dedup.....6178db424af75e75358f28160ea5a561