%0 Journal Article
%T Novel Indolocarbazole Derivative 12-(¦Á-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione Is a Preferred c-Myc Guanine Quadruplex Ligand
%A Dmitry N. Kaluzhny
%A Anna K. Shchyolkina
%A Nikolay S. Ilyinsky
%A Olga F. Borisova
%A Alexander A. Shtil
%J Journal of Nucleic Acids
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/184735
%X The indolocarbazole derivative 12-(¦Á-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (AIC) has demonstrated a high potency (at nanomolar to submicromolar concentrations) towards the NCI panel of human tumor cell lines and transplanted tumors. Intercalation into the DNA double helix has been identified as an important prerequisite for AIC cytotoxicity. In this study, we provide evidence for preferential binding to the G-quadruplex derived from the c-Myc oncogene promoter (Pu18 d(AG3TG4)2; G-c-Myc). The association constant for AIC:G-c-Myc complex was ~100 times and 10 times greater than the respective values for the complexes AIC:c-Myc duplex and AIC:telomeric d(TTAGGG)4 G-quadruplex. The concentrations at which AIC formed complexes with G-c-Myc were close to those that attenuated the steady-state level of the c-Myc mRNA in the human HCT116 colon carcinoma cell line. We suggest that preferential binding of AIC to G-c-Myc rather than to the c-Myc duplex might favor the quadruplex formation in the cells, thereby contributing to downregulation of the c-Myc expression by AIC. 1. Introduction The c-Myc oncoprotein is an important transcription factor that plays a pivotal role in cell proliferation and survival [1]. Deregulation of c-Myc gene expression has been detected in many tumor types and is believed to be an important step in tumorigenesis [2]. A major control element of the human c-Myc gene is a purine/pyrimidine rich region (Pu27; the nuclease-hypersensitive element 1) located 115 bases upstream from the P1 promoter. This element controls up to 95% of the total c-Myc transcription [3, 4]. The Pu27 segment has been shown to adopt an intramolecular DNA tetraplex (G-quadruplex) conformation under physiological conditions [5]. The oligomer containing four consecutive 3¡ä runs of guanines d(AGGGTGGGGAGGGTGGGG) (Pu18) is the minimal prerequisite for the c-Myc G-quadruplex (G-c-Myc) formation [6, 7]. Involvement of the G-quadruplex structures in regulation of gene transcription [8, 9], RNA metabolism [10] and telomere function [11] opens an area for design of small molecular weight compounds that can preferentially interact with G-quadruplex DNA. The distinctive nature of quadruplex topologies suggests that quadruplex ligands may selectively silence a given gene [8] with little effect on other DNA regions containing noncanonical higher-order structures. A number of G-quadruplex ligands have been designed that demonstrated either similar affinity to various G-quadruplexes or preferential binding to a particular tetraplex. For example, the
%U http://www.hindawi.com/journals/jna/2011/184735/