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c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach.
Biochim Biophys Acta Gen Subj. 2018 Mar; 1862(3):615-629.BB

Abstract

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.

Authors+Show Affiliations

Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, I-20133 Milano, Italy.Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, I-20133 Milano, Italy. Electronic address: stefania.mazzini@unimi.it.Fondazione IRCCS, Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milano, Italy.Molecular Targeting Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milano, Italy.Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, I-20133 Milano, Italy.Scientia Advice, di Roberto Artali, 20832 Desio, MB, Italy.Fondazione IRCCS, Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milano, Italy.Fondazione IRCCS, Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milano, Italy.Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, I-20133 Milano, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29229300

Citation

Musso, Loana, et al. "C-MYC G-quadruplex Binding By the RNA Polymerase I Inhibitor BMH-21 and Analogues Revealed By a Combined NMR and Biochemical Approach." Biochimica Et Biophysica Acta. General Subjects, vol. 1862, no. 3, 2018, pp. 615-629.
Musso L, Mazzini S, Rossini A, et al. C-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach. Biochim Biophys Acta Gen Subj. 2018;1862(3):615-629.
Musso, L., Mazzini, S., Rossini, A., Castagnoli, L., Scaglioni, L., Artali, R., Di Nicola, M., Zunino, F., & Dallavalle, S. (2018). C-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach. Biochimica Et Biophysica Acta. General Subjects, 1862(3), 615-629. https://doi.org/10.1016/j.bbagen.2017.12.002
Musso L, et al. C-MYC G-quadruplex Binding By the RNA Polymerase I Inhibitor BMH-21 and Analogues Revealed By a Combined NMR and Biochemical Approach. Biochim Biophys Acta Gen Subj. 2018;1862(3):615-629. PubMed PMID: 29229300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach. AU - Musso,Loana, AU - Mazzini,Stefania, AU - Rossini,Anna, AU - Castagnoli,Lorenzo, AU - Scaglioni,Leonardo, AU - Artali,Roberto, AU - Di Nicola,Massimo, AU - Zunino,Franco, AU - Dallavalle,Sabrina, Y1 - 2017/12/08/ PY - 2017/06/23/received PY - 2017/11/03/revised PY - 2017/12/07/accepted PY - 2017/12/13/pubmed PY - 2018/5/23/medline PY - 2017/12/13/entrez KW - Antitumor agents KW - BMH-21 KW - G-quadruplex KW - Molecular modelling KW - NMR KW - c-MYC SP - 615 EP - 629 JF - Biochimica et biophysica acta. General subjects JO - Biochim Biophys Acta Gen Subj VL - 1862 IS - 3 N2 - 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. SN - 0304-4165 UR - https://www.unboundmedicine.com/medline/citation/29229300/c_MYC_G_quadruplex_binding_by_the_RNA_polymerase_I_inhibitor_BMH_21_and_analogues_revealed_by_a_combined_NMR_and_biochemical_Approach_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-4165(17)30390-2 DB - PRIME DP - Unbound Medicine ER -