1. The Oncogenic Signaling Pathways in BRAF -Mutant Melanoma Cells are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands.
- Author
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Recagni M, Tassinari M, Doria F, Cimino-Reale G, Zaffaroni N, Freccero M, Folini M, and Richter SN
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Circular Dichroism, G-Quadruplexes drug effects, Gene Expression Regulation, Neoplastic genetics, Humans, Melanoma genetics, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-kit genetics, Signal Transduction genetics, Imides therapeutic use, Melanoma metabolism, Naphthalenes therapeutic use, Proto-Oncogene Proteins B-raf genetics, Signal Transduction physiology
- Abstract
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., Competing Interests: The authors declare no conflict of interest
- Published
- 2019
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