The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands
Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonic...
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doaj-e0f8297700c44f0f884ee03a444f0fc82020-11-25T02:22:58ZengMDPI AGCells2073-44092019-10-01810127410.3390/cells8101274cells8101274The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex LigandsMarta Recagni0Martina Tassinari1Filippo Doria2Graziella Cimino-Reale3Nadia Zaffaroni4Mauro Freccero5Marco Folini6Sara N. Richter7Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G.A. Amadeo 42, 20133 Milan, ItalyDepartment of Molecular Medicine, University of Padua, via A. Gabelli 63, 35121 Padua, ItalyDepartment of Chemistry, University of Pavia, v. le Taramelli 10, 27100 Pavia, ItalyDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G.A. Amadeo 42, 20133 Milan, ItalyDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G.A. Amadeo 42, 20133 Milan, ItalyDepartment of Chemistry, University of Pavia, v. le Taramelli 10, 27100 Pavia, ItalyDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G.A. Amadeo 42, 20133 Milan, ItalyDepartment of Molecular Medicine, University of Padua, via A. Gabelli 63, 35121 Padua, ItalyMelanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the <i>BRAFV600E</i>-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, <i>KIT</i> and <i>BCL-2</i>. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in <i>BRAF</i>-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of <i>BRAF</i>-mutant melanoma cells.https://www.mdpi.com/2073-4409/8/10/1274<i>bcl-2</i>g-quadruplex<i>kit</i>melanomanaphthalene diimidesoncogene promoter |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marta Recagni Martina Tassinari Filippo Doria Graziella Cimino-Reale Nadia Zaffaroni Mauro Freccero Marco Folini Sara N. Richter |
spellingShingle |
Marta Recagni Martina Tassinari Filippo Doria Graziella Cimino-Reale Nadia Zaffaroni Mauro Freccero Marco Folini Sara N. Richter The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands Cells <i>bcl-2</i> g-quadruplex <i>kit</i> melanoma naphthalene diimides oncogene promoter |
author_facet |
Marta Recagni Martina Tassinari Filippo Doria Graziella Cimino-Reale Nadia Zaffaroni Mauro Freccero Marco Folini Sara N. Richter |
author_sort |
Marta Recagni |
title |
The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands |
title_short |
The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands |
title_full |
The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands |
title_fullStr |
The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands |
title_full_unstemmed |
The Oncogenic Signaling Pathways in <i>BRAF</i>-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands |
title_sort |
oncogenic signaling pathways in <i>braf</i>-mutant melanoma cells are modulated by naphthalene diimide-like g-quadruplex ligands |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2019-10-01 |
description |
Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the <i>BRAFV600E</i>-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, <i>KIT</i> and <i>BCL-2</i>. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in <i>BRAF</i>-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of <i>BRAF</i>-mutant melanoma cells. |
topic |
<i>bcl-2</i> g-quadruplex <i>kit</i> melanoma naphthalene diimides oncogene promoter |
url |
https://www.mdpi.com/2073-4409/8/10/1274 |
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