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The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands

1
Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G.A. Amadeo 42, 20133 Milan, Italy
2
Department of Molecular Medicine, University of Padua, via A. Gabelli 63, 35121 Padua, Italy
3
Department of Chemistry, University of Pavia, v. le Taramelli 10, 27100 Pavia, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cells 2019, 8(10), 1274; https://doi.org/10.3390/cells8101274
Received: 25 July 2019 / Revised: 27 September 2019 / Accepted: 16 October 2019 / Published: 18 October 2019
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 BRAFV600E-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, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-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 BRAF-mutant melanoma cells. View Full-Text
Keywords: BCL-2; G-quadruplex; KIT; melanoma; naphthalene diimides; oncogene promoter BCL-2; G-quadruplex; KIT; melanoma; naphthalene diimides; oncogene promoter
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Recagni, M.; Tassinari, M.; Doria, F.; Cimino-Reale, G.; Zaffaroni, N.; Freccero, M.; Folini, M.; Richter, S.N. The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells Are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands. Cells 2019, 8, 1274.

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