Porphyrin Derivatives for Telomere Binding and Telomerase Inhibition

Dixon, Isabelle M.; Lopez, Fréderic; Estève, Jean-Pierre; Tejera, Águeda M.; Blasco, Marı́a A.; Pratviel, Geneviève; Meunier, Bernard

doi:10.1002/cbic.200400113

Cited by 128 publications

(96 citation statements)

References 40 publications

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“…41,68-70 For example, cationic porphyrins and sapphyrins have been shown to bind to and stabilize a number of different types of G-quadruplexes. 41,44,71,72 Specifically, the cationic porphyrin and sapphyrin used in this study, TMPyP4 and Se2SAP, have been shown to have variable selectivity for G-quadruplex structures. TMPyP4 is less discriminating compared to Se2SAP, which has been shown to specifically stabilize one of the c-myc G-quadruplexes, 41 as well as the K + form of the human telomeric G-quadruplex.…”

Section: Discussionmentioning

confidence: 99%

Deconvoluting the Structural and Drug-Recognition Complexity of the G-Quadruplex-Forming Region Upstream of the bcl-2 P1 Promoter

2006

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The human bcl-2 gene contains a GC-rich region upstream of the P1 promoter that has been shown to be critically involved in the regulation of bcl-2 gene expression. We have demonstrated that the guanine-rich strand of the DNA in this region can form any one of three distinct intramolecular Gquadruplex structures. Mutation and deletion analysis permitted isolation and identification of three overlapping DNA sequences within this element that formed the three individual G-quadruplexes. Each of these was characterized using nondenaturing gel analysis, DMS footprinting, and circular dichroism. The central G-quadruplex, which is the most stable, forms a mixed parallel/antiparallel structure consisting of three tetrads connected by loops of one, seven, and three bases. Three different G-quadruplex-interactive agents were found to further stabilize these structures, with individual selectivity toward one or more of these G-quadruplexes. Collectively, these results suggest that the multiple G-quadruplexes identified in the promoter region of the bcl-2 gene are likely to play a similar role to the G-quadruplexes in the c-myc promoter in that their formation could serve to modulate gene transcription. Last, we demonstrate that the complexity of the G-quadruplexes in the bcl-2 promoter extends beyond the ability to form any one of three separate G-quadruplexes to each having the capacity to form either three or six different loop isomers. These results are discussed in relation to the biological significance of this G-quadruplex-forming element in modulation of bcl-2 gene expression and the inherent complexity of the system where different G-quadruplexes and loop isomers are possible.

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Section: Discussionmentioning

confidence: 99%

Deconvoluting the Structural and Drug-Recognition Complexity of the G-Quadruplex-Forming Region Upstream of the bcl-2 P1 Promoter

2006

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“…For example, cationic porphyrins inhibit telomerase activity by binding a G-rich telomeric DNA fragment. This suppresses gene expression of c-myc and K-Ras by stabilizing a purine-rich G-quadruplex DNA structure (48,49). Although the S/E site of cyclin D1 is GC-rich, ZnPP did not preferentially bind to this region.…”

Section: Discussionmentioning

confidence: 99%

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and upregulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis. Zinc protoporphyrin IX (ZnPP)2 is a metabolite formed in trace amounts during heme biosynthesis. In this process, the final reaction is the chelation of zinc in the protoporphyrin ring, whereas heme is formed by chelation of iron in the ring. During periods of iron insufficiency or impaired iron utilization, ZnPP formation is enhanced. Clinically, ZnPP quantification is a sensitive and specific tool for measuring iron mineral status and metabolism (1). In addition, ZnPP regulates heme catabolism through competitively inhibiting the activity of heme oxygenase (HO), the rate-limiting enzyme in the heme degradation pathway that produces carbon monoxide and biliverdin. The latter is rapidly reduced to bilirubin by biliverdin reductase. Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3-6).Whereas ZnPP has been largely studied in relation to its inhibition of HO activity, reports show that ZnPP could exert cellular effects independent of HO activity (7,8). In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11). Although the underling mechanism is unknown, zinc mesoporphyrin, another analogue of heme, has been shown to induce HMOX1 expression by accelerating Bach1 protein degradation (12). Heme itself can affect gene expression by associating with transcription factors (13,14). Th...

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“…Several classes of small molecules have been identified to interact with and stabilize G-quadruplexes, including tricyclic anthraquinones (20), fluorenones (21), substituted acridines (22,23), cationic porphyrins (24,25), telomestatin (SOT-095; ref. 26), a perylenetetracarboxylic diimide derivative (27), indoloquinolines (28), pyridinedicarboxamide derivatives (29), and a benzonaphthofurandione tetracyclic compound (30).…”

Section: Introductionmentioning

confidence: 99%

G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells

Zhou

Deng

Zhang

et al. 2009

Molecular Cancer Therapeutics

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Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci γ-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5-induced γ-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of γ-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5. [Mol Cancer Ther 2009;8 (12):3203-13]

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Porphyrin Derivatives for Telomere Binding and Telomerase Inhibition

Cited by 128 publications

References 40 publications

Deconvoluting the Structural and Drug-Recognition Complexity of the G-Quadruplex-Forming Region Upstream of the bcl-2 P1 Promoter

Deconvoluting the Structural and Drug-Recognition Complexity of the G-Quadruplex-Forming Region Upstream of the bcl-2 P1 Promoter

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells

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