Background Pyridoquinazolinecarboxamides have been reported as RNA polymerase I inhibitors and represent a novel class of potential antitumor agents. BMH-21, was reported to intercalate with GC-rich rDNA, resulting in nucleolar stress as a primary mechanism of cytotoxicity. Methods The interaction of BMH-21 and analogues with DNA G-quadruplex structures was studied by NMR and molecular modelling. The cellular response was investigated in a panel of human tumor cell lines and protein expression was examined by Western Blot analysis. Results and conclusions We explored the ability of BMH-21 and its analogue 2 to bind to G-quadruplex present in the c-MYC promoter, by NMR and molecular modelling studies. We provide evidence that both compounds are not typical DNA intercalators but are effective binders of the tested G-quadruplex. The interaction with c-MYC G-quadruplex was reflected in down-regulation of c-Myc expression in human tumor cells. The inhibitory effect was almost complete in lymphoma cells SUDHL4 characterized by overexpression of c-Myc protein. This downregulation reflected an early and persistent modulation of cMyc mRNA. Given the relevance of c-MYC in regulation of ribosome biogenesis, it is conceivable that the inhibition of c-MYC contributes to the perturbation of nuclear functions and RNA polymerase I activity. Similar experiments with CX-5461, another RNA polymerase I transcription inhibitor, indicate the same behaviour in G-quadruplex stabilization. General significance Our results support the hypothesis that BMH-21 and analogue compounds share the same mechanism, i.e. G-quadruplex binding as a primary event of a cascade leading to inhibition of RNA polymerase I and apoptosis.
c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical approach / L. Musso, S. Mazzini, R. Anna, C. Lorenzo, L. Scaglioni, A. Roberto, D.N. Massimo, Z. Franco, S. Dallavalle. - In: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS. - ISSN 0304-4165. - 1862:3(2018 Mar), pp. 615-629.
|Titolo:||c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical approach|
MUSSO, LOANA (Primo)
MAZZINI, STEFANIA (Corresponding)
DALLAVALLE, SABRINA (Ultimo)
|Parole Chiave:||antitumor agents; BMH-21; c-MYC; G-quadruplex; molecular modelling; NMR; biophysics; biochemistry; molecular biology|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore CHIM/06 - Chimica Organica
|Data di pubblicazione:||mar-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bbagen.2017.12.002|
|Appare nelle tipologie:||01 - Articolo su periodico|