Targeting pancreatic cancer with a G-quadruplex ligand

Gunaratnam, Mekala; Fuente, María de la; Hampel, Sonja M.; Todd, Alan K.; Reszka, Anthony P.; Schätzlein, Andreas; Neidle, Stephen

doi:10.1016/j.bmc.2011.09.055

Cited by 61 publications

(59 citation statements)

References 41 publications

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“…This gives them the potential to inhibit transcription and translation of these oncogenes or cell-survival genes, which may have antiproliferative or anticancer effects. Investigation of transcription or translation inhibition is beyond the scope of this study, although it is notable that we previously showed BMSG-SH-5 (Gunaratnam et al, 2011) to bind to a promoter quadruplex in the HSP90 gene and also to downregulate the expression of the HSP90 protein in BMSG-SH-5-treated pancreatic cancer tumors. The accumulation of BMSG-SH-4 and -5 in nucleoli indicates interactions with rDNA, which may inhibit nucleolin binding, decrease the transcription of RNA polymerase I, and decrease ribosomal protein synthesis (Drygin et al, 2011).…”

Section: Mechanism Of Action Of G-quadruplex Ligandmentioning

confidence: 99%

“…We previously reported on a family of tetra-substituted naphthalene diimide (ND) ligands, which show elevated G-quadruplex DNA stabilization and potent antiproliferative activity in a panel of cancer cell lines (Cuenca et al, 2008;Gunaratnam et al, 2009;Hampel et al, 2010;Gunaratnam et al, 2011;Collie et al, 2012). We report here on studies of the cellular mechanism of action of three selected ND compounds from this family (BMSG-SH-3-5; Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1). Compound BMSG-SH-3 (N,N'-bis (3-(4-methylpiperazin-1-yl)propylamino)-2,6-bis(3-(4-methylpiperazin-1-yl)pentylamino)-1,2,5,8-naphthalenetetracarboxylic acid diimide) is the particular focus of this study since previous xenograft studies have demonstrated in vivo antitumor activity against the MIA-Pa-Ca-2 pancreatic cancer (Gunaratnam et al, 2011). It is shown here that this compound induces DNA damage and senescence, may inhibit protein synthesis, and may initiate genomic instability, which has an antimitotic effect.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

et al. 2012

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G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.

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Section: Mechanism Of Action Of G-quadruplex Ligandmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

et al. 2012

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“…To date, a diverse array of G-4 stabilizing compounds has been identified (17,18). Among them, numerous tri-and tetra-substituted naphthalene diimides (NDIs) have shown high affinity for telomeric G-4s and good antiproliferative activity in different experimental human tumor models (19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Nadai

Cimino‐Reale

Sattin

et al. 2014

International Journal of Oncology

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Abstract. 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-NMe 2 ) 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, telome rase 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-NMe 2 resulted in a cell type-dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H-NDI-NMe 2 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-NMe 2 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.

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“…[5] Down-regulation of transcription by small molecules that are able to induce and stabilise DNA G4 structures has been reported for oncogenes c-Myc, [6] c-Kit, [7] KRas, [8] and Hsp90, [9] reinforcing the concept that G4s are promising targets for the design of new compounds (G4 ligands) with potentially high cancer cell selectivity and lower toxicity than standard DNA-targeting anticancer drugs. [3a] Moreover, targeting G-quadruplexes in promoter oncogenes has several advantages over targeting expressed proteins, including the decreased likelihood of point mutations and resistance.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

et al. 2013

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G‐quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2‐b]quinolines mono‐, di‐, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5‐methyl or a 7‐carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7‐(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter‐G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c‐Kit2, 10‐fold selectivity for G4 over duplex DNA, and 100‐fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.

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Targeting pancreatic cancer with a G-quadruplex ligand

Cited by 61 publications

References 41 publications

Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

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