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Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells
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Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells
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Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells
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Journal Article
Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells
2015
Overview
Naphthalene diimide (NDI) derivatives have shown high affinity for telomeric guanine (G)-quadruplexes and good antiproliferative activity in different human tumor experimental models. A trisubstituted compound (H-NDI-NMe2) has been reported to stabilize the telomeric G-quadruplex and to cause telomere dysfunction and downregulation of telomerase expression. We further investigated its mechanism of action by analyzing the capability of the molecule to interfere with the expression levels of oncogenes, such as MYC, telomerase reverse transcriptase (TERT), KIT and BCL2, known to bear G-quadruplex-forming sequences within their promoters, in human tumor cell lines of different histological origin. Exposure to H-NDI-NMe2 resulted in a cell type-dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H-NDI-NMe2 bound with high affinity and effectively stabilized mainly MYC and BCL2, which share long sequences and the possibility of multiple G-quadruplex folding. The mRNA levels of both genes, but not protein amounts were affected by NDI treatment. Global gene expression analysis showed modulation of genes implicated in telomere function and mechanisms of cancer; however, G-quadruplex-mediated regulation of gene expression by H-NDI-NMe2 was largely dependent on the cell context. These data indicate that a deeper knowledge on the molecular mechanisms and biological effects of G-quadruplex structures is still needed to help developing new effective anticancer agents.
