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Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

Collery P, Mohsen A, Kermagoret A, Corre S, Bastian G, Tomas A, Wei M, Santoni F, Guerra N, Desmaële D, d'Angelo J - Invest New Drugs (2015)

Bottom Line: We now disclose an improved synthesis of this complex.Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d.We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

View Article: PubMed Central - PubMed

Affiliation: Société de Coordination de Recherches Thérapeutiques, Algajola, France, philippe.collery@gmail.com.

ABSTRACT
Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of complex 1
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Fig1: Chemical structure of complex 1

Mentions: Metal-based drugs have received increasing attention in recent years. The use of metals is indeed very attractive, as they offer unique spectrum of reactivity through ligand exchange and redox processes that is not available in the more common organic-based drugs. The discovery of the anticancer properties of cisplatin during the 1960s spurred the quest for alternative anticancer drugs with less side-effects. Beside platinum analogues including platinum (II) and (IV) derivatives, other metals have been recently explored, such as gallium, ruthenium, iron, gold, titanium or palladium [1]. In this context, rhenium-based drugs appeared as promising candidates for clinical development. Over the past years a growing number of studies have revealed the potential of Re organometallic complexes as anti-cancer agents. A recent review has been published with a particular emphasis on the cellular uptake and the localization of the currently known Re organometallic complexes as well as their potential mechanism of action [2]. Among Re organometallic complexes, several Re carbonyl complexes have been found to display cytotoxicity against breast cancer cell lines. For example, a Re(tricarbonyl)pentylcarbonato compound able to fight triple node negative human breast cancer cell lines has been described [3]. Nevertheless, despite the design of very efficient potent anti-cancer agents, very few in vivo studies have been conducted on cold Re organometallic complexes. On the other hand, it is noteworthy that some Se-based drugs have demonstrated a selective cytotoxicity against cancerous cells [4–6]. The tumor-specific cytotoxic effects of Se, with special emphasis on cascades of cellular events induced by pharmacologically active Se compounds have been recently reviewed [7]. It appears that certain redox-activated Se compounds induce complex cascades of pro-death signaling at pharmacological concentrations with superior tumor specificity, and that the target molecules are often implicated in drug resistance. With the aim to combine the antiproliferative properties of Re with the unique apoptotic modulator properties of Se we have recently designed the rhenium(I)-diselenoether complex 1 in which a central Re atom is coordinated with two Se atoms (Fig. 1). Complex 1 was shown to exhibit remarkable cytotoxicity against MCF-7 breast cancer cell lines [8]. The uptake and efflux of Re in malignant cells exposed to complex 1 have been reported, together with evidence of the incorporation of Re into the nucleus. Furthermore, tissue distribution of Re and Se after oral administration of 1 to mice have been reported [9].Fig. 1


Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

Collery P, Mohsen A, Kermagoret A, Corre S, Bastian G, Tomas A, Wei M, Santoni F, Guerra N, Desmaële D, d'Angelo J - Invest New Drugs (2015)

Chemical structure of complex 1
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4491361&req=5

Fig1: Chemical structure of complex 1
Mentions: Metal-based drugs have received increasing attention in recent years. The use of metals is indeed very attractive, as they offer unique spectrum of reactivity through ligand exchange and redox processes that is not available in the more common organic-based drugs. The discovery of the anticancer properties of cisplatin during the 1960s spurred the quest for alternative anticancer drugs with less side-effects. Beside platinum analogues including platinum (II) and (IV) derivatives, other metals have been recently explored, such as gallium, ruthenium, iron, gold, titanium or palladium [1]. In this context, rhenium-based drugs appeared as promising candidates for clinical development. Over the past years a growing number of studies have revealed the potential of Re organometallic complexes as anti-cancer agents. A recent review has been published with a particular emphasis on the cellular uptake and the localization of the currently known Re organometallic complexes as well as their potential mechanism of action [2]. Among Re organometallic complexes, several Re carbonyl complexes have been found to display cytotoxicity against breast cancer cell lines. For example, a Re(tricarbonyl)pentylcarbonato compound able to fight triple node negative human breast cancer cell lines has been described [3]. Nevertheless, despite the design of very efficient potent anti-cancer agents, very few in vivo studies have been conducted on cold Re organometallic complexes. On the other hand, it is noteworthy that some Se-based drugs have demonstrated a selective cytotoxicity against cancerous cells [4–6]. The tumor-specific cytotoxic effects of Se, with special emphasis on cascades of cellular events induced by pharmacologically active Se compounds have been recently reviewed [7]. It appears that certain redox-activated Se compounds induce complex cascades of pro-death signaling at pharmacological concentrations with superior tumor specificity, and that the target molecules are often implicated in drug resistance. With the aim to combine the antiproliferative properties of Re with the unique apoptotic modulator properties of Se we have recently designed the rhenium(I)-diselenoether complex 1 in which a central Re atom is coordinated with two Se atoms (Fig. 1). Complex 1 was shown to exhibit remarkable cytotoxicity against MCF-7 breast cancer cell lines [8]. The uptake and efflux of Re in malignant cells exposed to complex 1 have been reported, together with evidence of the incorporation of Re into the nucleus. Furthermore, tissue distribution of Re and Se after oral administration of 1 to mice have been reported [9].Fig. 1

Bottom Line: We now disclose an improved synthesis of this complex.Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d.We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

View Article: PubMed Central - PubMed

Affiliation: Société de Coordination de Recherches Thérapeutiques, Algajola, France, philippe.collery@gmail.com.

ABSTRACT
Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

No MeSH data available.


Related in: MedlinePlus