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

Abstract

SummaryRhenium (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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-015-0265-z) contains supplementary material, which is available to authorized users.

Negative Impact of Total Body Irradiation on the Antitumor Activity of Rhenium-(I)-diselenoether

“…The results of this study are unexpected as they did not confirm the antitumor activity of the Re-diselenoether compound reported in two previous studies (5,6), with the same experimental model of MDA-MB231-transplanted tumors in nude mice treated with the same dose of 10 mg/kg/d of Re-diselenoether. Differences in the experimental conditions may partly explain the difference of results between three experiments.…”

“…Due to the irradiation, the use of matrigel and the great number of transplanted tumor cells, the tumor volumes were 10 times greater in this study (200 mm 3 ) at the beginning of treatments than in the previously published one (5), where the tumors were of about only 20 mm 3 . In this study, the tumor cells were subcutaneously injected, not into the fat mammary pad and without induction of metastases, but with rapid growth of the primary tumor, reaching 2,000 mm 3 at the end of the experiment.…”

“…It was also shown that the Re-diselenoether formed mono-adducts and bisadducts with a methyl-guanine, but also liberated the weakly chelating diselenoether ligand [supplementary material in (5)]. Therefore we can hypothesize that while the Re core will have a role by interacting with DNA guanine bases, the diselenoether ligand will take Se to other targets.…”

“…It is known that Re is able to bind DNA reversibly and that Re is found in the nucleus of malignant cells after the administration of Re-diselenoether (1,5). It was also shown that the Re-diselenoether formed mono-adducts and bisadducts with a methyl-guanine, but also liberated the weakly chelating diselenoether ligand [supplementary material in (5)].…”

“…The anticancer activity of Re-diselenother has been demonstrated in experimental models of resistant triplenegative breast tumors (MDA-MB231), in malignant cells in culture, as well as after oral (5) or intraperitoneal administration (6) to tumor-bearing mice, at a daily dose of 10 mg/kg/day for 4 weeks, which was safe for the animals. The Re-diseleno ether compound we used, constituted an original chemical combination, and we aimed to complete the investigation of its biological role in an experimental model of cancer.…”