Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products

Melvin, Matt S.; Wooton, Katie E; Rich, Cassandra C; Saluta, Gilda; Kucera, Gregory L.; Lindquist, Niels; Manderville, Richard A.

doi:10.1016/s0162-0134(01)00338-5

Cited by 69 publications

(57 citation statements)

References 44 publications

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“…The molecular mechanism of prodigiosin cytotoxicity seems to be complex as it alters several biological processes of potential importance to cell viability. For example, prodigiosin has been shown to modulate intracellular pH through lysosomal alkalinization (11,12), inhibit cell proliferation via G 1 -S transition arrest (13), and interact with DNA inducing single-and double-strand breaks and topoisomerase I and II inhibition (14,15).…”

Section: Introductionmentioning

confidence: 99%

Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells

Soto‐Cerrato

Viñals²,

Lambert³

et al. 2007

Molecular Cancer Therapeutics

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Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) is a bacterial metabolite that has anticancer and antimetastatic properties. However, the molecular mechanisms responsible for these abilities are not fully understood. Gene expression profiling of the human breast cancer cell line MCF-7 treated with prodigiosin was analyzed by cDNA array technology. The majority of the significantly modified genes were related to apoptosis, cell cycle, cellular adhesion, or transcription regulation. The dramatic increase of the nonsteroidal anti-inflammatory drugactivated gene 1 (NAG-1) made this gene an interesting candidate regarding the possible mechanism by which prodigiosin induces cytotoxicity in MCF-7 cells. Our results show that prodigiosin triggers accumulation of the DNAdamage response tumor-suppressor protein p53 but that NAG-1 induction was independent of p53 accumulation. Moreover, prodigiosin caused AKT dephosphorylation and glycogen synthase kinase-3B (GSK-3B) activation, which correlated with NAG-1 expression. Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3B, which might be due, at least in part, to the blockade of the GSK-3B -dependent up-regulation of death receptors 4 and 5 expression. These findings suggest that prodigiosinmediated GSK-3B activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent. [Mol Cancer Ther 2007;6(1):362 -9]

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Section: Introductionmentioning

confidence: 99%

Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells

Soto‐Cerrato

Viñals²,

Lambert³

et al. 2007

Molecular Cancer Therapeutics

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“…Functionalized C-ring prodigiosins have been shown to have improved antimalarial, chloride transport and DNA cleavage activity 12,65 . The prodigiosins also show anti-cancer activity which is thought to be due to a combination of their H + /Cl -transport and their ability to bind to DNA and cause copper-mediated double-strand DNA cleavage 19,66 .…”

Section: Characterization Dna Binding and Cleavage Activity Of A Newmentioning

confidence: 99%

“…Prodigiosin has also been shown to efficiently bind DNA and facilitate oxidative DNA cleavage in the presence of Cu(II). This DNA cleavage occurs without the need of an added reductant in a mechanism that is dependent on oxidation of the electron-rich pyrrolylpyrromethene moiety 66 . In this work we investigated the interaction of a prodigiosin analogue, 1 (figure 18), with Cu 2+ and showed that 1 forms a metalloprodigiosin complex (1·Cu) which is oxidized on the C-pyrrole ring and is able to bind to and cleave DNA.…”

Section: Characterization Dna Binding and Cleavage Activity Of A Newmentioning

confidence: 99%

Characterization, DNA Binding and Cleavage Activities of New Prodigiosin and Tambjamine Analogues and Their Cu²⁺ and Zn²⁺ Complexes

Chichetu¹

2000

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Prodigiosins and tambjamines are natural compounds from bacterial and marine sources belonging to a family containing a common 4-methoxy-2,2'-bipyrrole core.These compounds have received a lot of interest due to their promising biological activities. Studies have suggested DNA as a potential therapeutic target for the natural prodigiosin and tambjamine due to their ability to facilitate oxidative DNA cleavage in the presence of Cu 2+ . Based on this we sought to study the metal binding activity of new prodigiosin and tambjamine analogues. A new prodigiosin analogue was synthesized and complexed with Cu 2+ . This revealed 1:1 complex formation between the tripyrrole and Cu 2+ that was confirmed by mass spectra and NMR spectra analysis. In addition in situ studies also revealed that our new analogues of prodigiosin cannot bind Zn 2+ when the methoxy group on ring B is replaced by an alkyl group or when one of the ring nitrogens is methylated.Our UV-Vis experiments with calf thymus DNA showed that prodigiosins and tambjamines bind DNA mainly through an external mode, suggesting that hydrogen bonding between the pyrrole ring nitrogens and the bases of DNA takes precedence over stacking interactions. For the new Cu 2+ complex synthesized however, we observed spectral changes that suggest intercalation into DNA.DNA cleavage experiments revealed that the prodigiosin-Cu complex is able to convert supercoiled DNA into its linear form. The data from the gel shift assays fit well to a first-order consecutive reaction model. In addition to preformed metal complexes, we showed DNA cleavage by in situ complexation of the ligands in the

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“…Prodigiosin itself has considerable immunosuppressive activity, antibacterial, antimycotic and antimalarial activity, etc. [3,22,26], but high toxicity precludes its application as a therapeutic agent. In recent years, the research on PG aimed mainly at its potential as a drug to resist tumor in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Study on the interaction of Prodigiosin with bovine serum albumin by spectroscopic methods

et al. 2012

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Abstract. The interaction between bovine serum albumin (BSA) and Prodigiosin (PG) was investigated by UV-vis absorption, fluorescence, synchronous fluorescence, FT-IR and circular dichroism (CD) techniques. The data of UV-vis absorption and fluorescence spectra displayed that there existed interaction between PG and aromatic amino acid residues of BSA. The synchronous fluorescence and CD spectrum experiment both showed that the secondary structure of BSA changed with addition of PG. All these results revealed that the conformation and microenvironment of BSA were changed.

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Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products

Cited by 69 publications

References 44 publications

Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells

Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells

Characterization, DNA Binding and Cleavage Activities of New Prodigiosin and Tambjamine Analogues and Their Cu²⁺ and Zn²⁺ Complexes

Study on the interaction of Prodigiosin with bovine serum albumin by spectroscopic methods

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