Protein kinase C inhibitor anchored BRD4 PROTAC PEGylated nanoliposomes for the treatment of vemurafenib-resistant melanoma

Exp Cell Res. 2020 Nov 1;396(1):112275. doi: 10.1016/j.yexcr.2020.112275. Epub 2020 Sep 6.

Abstract

Limited treatment options and development of resistance to targeted therapy within few months pose significant challenges in the treatment of BRAF-mutated malignant melanoma. Moreover, extensive angiogenesis and vasculogenic mimicry promote the rapid progression of disease. The purpose of this study was to develop a protein kinase C inhibitor anchored BRD4 PROTAC (ARV) loaded PEGylated nanoliposomes (LARPC). Palmitoyl-dl-carnitine chloride (PC) was used as a protein kinase C inhibitor to provide a cationic surface charge to LARPC. The formulation was characterized for particle size, zeta potential, drug release and various cell culture assays using HUVEC and vemurafenib resistant melanoma cells. The particle size of LARPC was found to be 105.25 ± 2.76 nm with a zeta potential of +26.6 ± 6.25 mV. Inhibition of angiogenesis was demonstrated by ARV and LARPC using human umbilical vein endothelial cells (HUVEC)-based matrigel basement membrane model. Additionally, LARPC demonstrated very low IC50 with promising inhibition of vasculogenic mimicry channel formation, cell migration as well as colony formation in vemurafenib-resistant melanoma cell lines. Hence, the outcome of this combination therapy indicated the suitability of LARPC as a potential and novel approach for eradicating vemurafenib-resistant melanoma.

Keywords: ARV; PEGylated nanoliposomes; Palmitoyl-dl-Carnitine chloride; Protein kinase C inhibitor; Vemurafenib-resistant melanoma.

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Liposomes* / chemical synthesis
  • Liposomes* / metabolism
  • Melanocytes* / drug effects
  • Melanocytes* / metabolism
  • Melanocytes* / pathology
  • Models, Biological
  • Mutation
  • Nanocapsules / chemistry
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / prevention & control
  • Palmitoylcarnitine / metabolism
  • Palmitoylcarnitine / pharmacology
  • Polyethylene Glycols / chemistry
  • Protein Kinase C* / antagonists & inhibitors
  • Protein Kinase C* / genetics
  • Protein Kinase C* / metabolism
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Signal Transduction
  • Static Electricity
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Vemurafenib* / pharmacology

Substances

  • Antineoplastic Agents
  • BRAF protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Liposomes
  • Nanocapsules
  • Palmitoylcarnitine
  • Polyethylene Glycols
  • Protein Kinase C
  • Proto-Oncogene Proteins B-raf
  • Transcription Factors
  • Vemurafenib