Improving the bioactivity of Zn(ii)-curcumin based complexes

Pucci, Daniela; Crispini, Alessandra; Mendiguchía, Bárbara Sanz; Pirillo, Sante; Ghedini, Mauro; Morelli, Sabrina; Bartolo, Loredana De

doi:10.1039/c3dt50513h

Cited by 95 publications

(84 citation statements)

References 31 publications

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“…These results support the findings that Zn-curc treatment was indeed restoring wtp53 transcriptional activity. As Zn-cur complex previously showed increased biological activity compared to curcumin alone [13,14], here we tested the effect of curcumin (curc) on p53 reactivation. We found that curcumin alone did not induce wtp53 target gene transcription (Figure 2F), suggesting that the effect of Zn-curc on mtp53 reactivation was mainly depended on Zn(II) ability to induce mtp53 reactivation.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we took advantage of the fluorescent feature of the Zn-curc compound [13,14] to evaluate its intratumoral localization. To this aim we used human U373 glioblastoma cells engineered with luciferase reporter (U373-LUC) for imaging analysis [22].…”

Section: Resultsmentioning

confidence: 99%

“…Here we attempted to evaluate the effect of a novel Zinc(II) compound containing a 4,4′-disubstituted-2,2′-bipyridine as main ligand and curcumin and chloride as ancillary ligands [13,14]. As for ZnCl 2 , Zn-curc modified the equilibrium between p53 mutant and wild-type conformation toward wild-type conformation, specifically affecting R175H and R273H mutant proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Although we found that ZnCl 2 treatment did not induce cell death by itself, it restored mt-p53-carrying cell sensitivity to chemotherapy allowing tumor regression [9-12]. Here we aimed at examine the effect of a novel Zinc compound, a heteroleptic pentacoordinated (bpy-9)Zn(curc, Cl) complex (hereafter indicated as Zn-curc) containing a 4,4’-disubstituted-2,2′-bipyridine as main ligand and curcumin (curc) and chloride (Cl) as ancillary ligands [13,14], in mutant p53-carrying cancer cells. The presence of the curcumin framework in the Zn-curc complex allows intrinsic fluorescence activity, therefore we attempted to exploit this feature to evaluate the intratumoral distribution of Zn-curc in an ortothopic model of glioblastoma in mice.…”

Section: Introductionmentioning

confidence: 99%

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A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells

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Porru

et al. 2013

J Exp Clin Cancer Res

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BackgroundMutations of the p53 oncosuppressor gene are amongst the most frequent aberration seen in human cancer. Some mutant (mt) p53 proteins are prone to loss of Zn(II) ion that is bound to the wild-type (wt) core, promoting protein aggregation and therefore unfolding. Misfolded p53 protein conformation impairs wtp53-DNA binding and transactivation activities, favouring tumor growth and resistance to antitumor therapies. Screening studies, devoted to identify small molecules that reactivate mtp53, represent therefore an attractive anti-cancer therapeutic strategy. Here we tested a novel fluorescent curcumin-based Zn(II)-complex (Zn-curc) to evaluate its effect on mtp53 reactivation in cancer cells.MethodsP53 protein conformation was examined after Zn-curc treatment by immunoprecipitation and immunofluorescence assays, using conformation-specific antibodies. The mtp53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The intratumoral Zn-curc localization was evaluated by immunofluorescence analysis of glioblastoma tissues of an ortothopic mice model.ResultsThe Zn-curc complex induced conformational change in p53-R175H and -R273H mutant proteins, two of the most common p53 mutations. Zn-curc treatment restored wtp53-DNA binding and transactivation functions and induced apoptotic cell death. In vivo studies showed that the Zn-curc complex reached glioblastoma tissues of an ortothopic mice model, highlighting its ability to crossed the blood-tumor barrier.ConclusionsOur results demonstrate that Zn-curc complex may reactivate specific mtp53 proteins and that may cross the blood-tumor barrier, becoming a promising compound for the development of drugs to halt tumor growth.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells

Garufi

Trisciuoglio

Porru

et al. 2013

J Exp Clin Cancer Res

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“…22, 23, 24, 25, 26, 27 However, whether zinc supplementation might also affect mutp53 protein levels has never been addressed. Here, we asked whether a novel curcumin-based zinc compound (Zn(II)-curc), 28, 29 able to reactivate mutp53 proteins, 27 could modify mutp53 stability. We specifically analyzed conformation defective R175H p53 mutant (p53H175) because it is one of the most frequently and vastly studied p53 mutant, which not only exhibits dominant-negative activities over wtp53 but also possesses GOF properties.…”

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confidence: 99%

Degradation of mutant p53H175 protein by Zn(II) through autophagy

et al. 2014

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TP53, one of the most important oncosuppressors, is frequently mutated in cancer. Several p53 mutant proteins escape proteolytic degradation and are highly expressed in an aberrant conformation often acquiring pro-oncogenic activities that promote tumor progression and resistance to therapy. Therefore, it has been vastly proposed that reactivation of wild-type (wt) function(s) from mutant p53 (mutp53) may have therapeutic significance. We have previously reported that Zn(II) restores a folded conformation from mutp53 misfolding, rescuing wild-type (wt) p53/DNA-binding and transcription activities. However, whether Zn(II) affects mutp53 stability has never been investigated. Here we show that a novel Zn(II) compound induced mutp53 (R175H) protein degradation through autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins. Accordingly, pharmacological or genetic inhibition of autophagy prevented Zn(II)-mediated mutp53H175 degradation as well as the ability of the Zn(II) compound to restore wtp53 DNA-binding and transcription activity from this mutant. By contrast, inhibition of the proteasome failed to do so, suggesting that autophagy is the main route for p53H175 degradation. Mechanistically, Zn(II) restored the wtp53 ability to induce the expression of the p53 target gene DRAM (damage-regulated autophagy modulator), a key regulator of autophagy, leading to autophagic induction. Accordingly, inhibition of wtp53 transactivation by pifithrin-α (PFT-α) impaired both autophagy and mutp53H175 degradation induced by curcumin-based zinc compound (Zn(II)-curc). Viewed together, our results uncover a novel mechanism employed by Zn(II)-curc to reactivate mutp53H175, which involves, at least in part, induction of mutp53 degradation via wtp53-mediated autophagy.

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