Conjugated eicosapentaenoic acid inhibits human topoisomerase IB with a mechanism different from camptothecin

Castelli, Silvia; Campagna, Alessia; Vassallo, Oscar; Tesauro, Cinzia; Fiorani, Paola; Tagliatesta, Pietro; Oteri, Francesco; Falconi, Mattia; Majumder, Hemanta K.; Desideri, Alessandro

doi:10.1016/j.abb.2009.04.007

Cited by 29 publications

(25 citation statements)

References 29 publications

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“…Preincubation of the enzyme with cEPA does not change the results reported in Fig. (1), at variance on what observed with the human enzyme, where a complete inhibition was observed only after pre-incubation of cEPA with the enzyme [38]. The antiprotozoal activity of cEPA has been investigated measuring its toxicity against L.donovani promastigotes and as a control against murine macrophages.…”

Section: Resultsmentioning

confidence: 89%

“…cEPA has been shown to interact with human topoisomerase, however in the case of the human enzyme complete inhibition was never observed when DNA, enzyme and cEPA were mixed together up to 300 μM cEPA concentration [38], whilst in the case of L. donovani topoisomerase complete inhibition is observed at 100 μM Fig. (1).…”

Section: Discussionmentioning

confidence: 98%

“…In the large subunit three residues of the catalytic pentad, Arg314, Lys352 and Arg410, interact with cEPA and interactions are also observed with Lys272 and Lys407, that correspond to Lys443, Lys587 of the human enzyme sequence. These last two residues have been shown to be involved in the interaction of cEPA with human topoisomerase IB, where cEPA inhibits the human enzyme only upon preincubation [38].…”

Section: Resultsmentioning

confidence: 99%

“…(1). For the human enzyme fully inhibition is only observed upon preincubation of the enzyme with cEPA [38]. Docking of cEPA with the leishmanial enzyme has shown that the compound is able to directly interact with the catalytic Tyr222 and with several residues located in proximity of the active site Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Recently we have shown that another fatty acid, namely conjugated eicosapentaenoic acid (cEPA) has an inhibitory effect on human topoisomerase [38] and this is likely the molecular reason it inhibits the cell growth of human tumor cell lines, while it has not effect on human fibroblast cell lines [39][40][41]. In this work, in order to compare similarities and differences between the human and L. donovani topoisomerase I, we have investigated the effect of cEPA on both the purified enzymes and on L. donovani promastigotes in comparison to murine macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Desideri¹

2011

TOANTIMJ

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Conjugated eicosapentaenoic acid inhibits the relaxation activity of purified L. donovani topoisomerase I, with an efficiency higher than that displayed by the corresponding human enzyme. Docking of the acid compound over the 3D structure of the enzyme shows that the complex is stabilized by a large network of interaction between the compound and many residues located in proximity of the active site, including the catalytic tyrosine 222, providing an explanation for its efficient inhibitory effect. The acid has also a strong antiprotozoal activity against L. donovani promastigotes ( EC 50 = 75 M) whilst it has no effect against murine macrophages (IC 50 2 mM). Taken together the results indicate that L. donovani topoisomerase I can be considered an interesting molecular target and that conjugated eicosapentaenoic acid can be taken in consideration as a possible lead compound against leishmaniasis.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Desideri¹

2011

TOANTIMJ

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Kinetic and thermodynamic analysis of 9‐nitrocamptothecin hydrolysis at physiological pH in the presence and absence of human serum albumin

Saha

Kunadharaju

Savva

2010

Int J of Chemical Kinetics

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Kinetic and thermodynamic analysis of the 9-nitrocamptothecin (9NC) hydrolysis reaction in the presence and absence of human serum albumin (HSA) in phosphate-buffered saline (PBS) of pH 7.4 was carried out by first derivative absorption spectroscopy. The thermodynamic parameters determined in these studies provided a mechanistic explanation toward the endothermic but yet thermodynamically favorable hydrolysis of 9NC at physiological temperature and pH. In the presence of HSA, the apparent rate constant of 9NC hydrolysis was 3-3.5 times higher than in 9NC solutions alone, whereas the apparent equilibrium constant of 9NC hydrolysis was found to increase at a higher extent in the presence of HSA than in PBS with increasing temperature, reaching almost complete hydrolysis of the 9NC to the 9NC-carboxylate at 315.15 K. Importantly, the E a of the 9NC hydrolysis reaction in the presence of HSA was determined to be on average 17 kJ mol −1 lower than the E a determined in plain PBS. Moreover, analysis of binding isotherms constructed for the HSA interaction with 9NC, using infinitely cooperative and independent binding models, demonstrated an incredibly higher binding constant for the 9NC-carboxylate form as compared to the very weak and concentration-dependent binding for the 9NC-lactone species at 310.15 K. Taken together, the preferential association of the carboxylate form with HSA and the lower E a of 9NC hydrolysis in the presence of HSA provide a mechanistic explanation for the shift of lactone-carboxylate equilibria toward the carboxylate product under physiological conditions of pH and ionic strength. C

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Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

Carballeira

Montano

Amador

et al. 2015

Lipids

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The novel fatty acids (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic acid (1a) and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid (1b) were isolated in 80% purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography-mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP-1 and HepG2 cells with EC50’s between 41 and 35 μg/mL. Apoptosis was not the preferred mode of cell death induced by 1a–1b in the THP-1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC50 = 1.8 μg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC50 = 0.17 mg/mL) and free living promastigotes (IC50 = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC50 = 5.1 μg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.

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Conjugated eicosapentaenoic acid inhibits human topoisomerase IB with a mechanism different from camptothecin

Cited by 29 publications

References 29 publications

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Conjugated Eicosapentaenoic Acid (cEPA) Inhibits L. donovani Topoisomerase I and has an Antiproliferative Activity Against L. donovani Promastigotes

Kinetic and thermodynamic analysis of 9‐nitrocamptothecin hydrolysis at physiological pH in the presence and absence of human serum albumin

Novel Very Long‐Chain α‐Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB

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