Abstract
Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation.
Keywords:
A11; Akt; MAPK; Melanocyte differentiation; Melanoma; mitf.
Copyright © 2017 Elsevier Inc. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Cell Differentiation / drug effects*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Dose-Response Relationship, Drug
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Melanocytes / drug effects*
-
Melanocytes / metabolism
-
Melanocytes / pathology
-
Melanoma, Experimental / genetics
-
Melanoma, Experimental / metabolism
-
Melanoma, Experimental / pathology
-
Mice
-
Microphthalmia-Associated Transcription Factor / genetics
-
Microphthalmia-Associated Transcription Factor / metabolism
-
Mitogen-Activated Protein Kinases / metabolism
-
Mitosis / drug effects
-
PAX3 Transcription Factor / genetics
-
PAX3 Transcription Factor / metabolism
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction / drug effects
-
Skin Neoplasms / drug therapy*
-
Skin Neoplasms / genetics
-
Skin Neoplasms / metabolism
-
Skin Neoplasms / pathology
-
Stilbenes / pharmacology*
-
Zebrafish / embryology
-
Zebrafish Proteins / genetics
-
Zebrafish Proteins / metabolism
Substances
-
Antineoplastic Agents
-
Microphthalmia-Associated Transcription Factor
-
PAX3 Transcription Factor
-
Stilbenes
-
Zebrafish Proteins
-
pax3a protein, zebrafish
-
Proto-Oncogene Proteins c-akt
-
Mitogen-Activated Protein Kinases