One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing suitable carrier proteins. Thus, thiolated human serum transferrin was conjugated with four maleimide derivatives of doxorubicin that differed in the stability of the chemical link between drug and spacer. Of the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond, and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive transferrin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable to that of the free drug (employing the BrdU (5-bromo-2'-deoxyuridine) incorporation assay and tritiated thymidine incorporation assay, respectively, IC50 approximately 0.1-1 mM), whereas conjugates with the amide derivatives showed no activity. Furthermore, antiproliferative activity of the most active transferrin conjugate (i.e. the conjugate containing a benzoyl hydrazone link) was demonstrated in the LXFL 529 lung carcinoma cell line employing a sulforhodamine B assay. In contrast to in vitro studies in tumor cells, cell culture experiments performed with human endothelial cells (HUVEC) showed that the acid-sensitive transferrin conjugates of doxorubicin were significantly less active than free doxorubicin (IC50 values approximately 10-40 higher by the BrdU incorporation assay), indicating selectivity of the doxorubicin-transferrin conjugates for tumor cells. Fluorescence microscopy studies in the MDA-MB-468 breast cancer cell showed that free doxorubicin accumulates in the cell nucleus, whereas doxorubicin of the transferrin conjugates is found localized primarily in the cytoplasm. The differences in the intracellular distribution between transferrin-doxorubicin conjugates and doxorubicin were confirmed by laser scanning confocal microscopy in LXFL 529 cells after a 24 h incubation that revealed an uptake and mode of action other than intercalation with DNA. The relationship between stability, cellular uptake, and cytotoxicity of the conjugates is discussed.
A new dirhenium(III) complex cis-[Re2(GABA)2Cl5(H2O)]Cl.2H2O with zwitterionic gamma-aminobutyrate ligands was prepared and characterized by spectral methods and crystallography. The structure of the compound is comprised of dinuclear complex cations (Re-Re 2.2437(3) A) involving cis-oriented double carboxylate bridges, four equatorial chloride ions and two weakly bonded aqua and chloride ligands in the axial positions at two rhenium centers (Re-O 2.363(3), Re-Cl 2.6735(12) A). Antitumor properties of the complex were studied in the model of tumor growth with the use of Wistar rats inoculated by tumor carcinoma Guerink cells. The introduction of the compound in dosage according to the scheme of antioxidant therapy, inhibited the tumor growth by ca. 60% and led to stabilization of red blood cells in the tumor-bearing organisms. The combined introduction of the compound and cisplatin had a significant impact on the tumor growth and the disappearance of the tumors in most of the animals.
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.
Background: Many rhenium (Re) complexes with potential anticancer properties have been synthesized in the recent years with the aim to overcome the clinical limitations of platinum agents. Re(I) tricarbonyl complexes are the most common but Re compounds with higher oxidation states have also been investigated, as well as hetero-metallic complexes and Re-loaded self-assembling devices. Many of these compounds display promising cytotoxic and phototoxic properties against malignant cells but all Re compounds are still at the stage of preclinical studies. Methods: The present review focused on the rhenium based cancer drugs that were in preclinical and clinical trials were examined critically. The detailed targeted interactions and experimental evidences of Re compounds reported by the patentable and non-patentable research findings used to write this review. Results: In the present review, we described the most recent and promising rhenium compounds focusing on their potential mechanism of action including, phototoxicity, DNA binding, mitochondrial effects, oxidative stress regulation or enzyme inhibition. Many ligands have been described that modulating the lipophilicity, the luminescent properties, the cellular uptake, the biodistribution, and the cytotoxicity, the pharmacological and toxicological profile. Conclusion: Re-based anticancer drugs can also be used in targeted therapies by coupling to a variety of biologically relevant targeting molecules. On the other hand, combination with conventional cytotoxic molecules, such as doxorubicin, allowed to take into profit the targeting properties of Re for example toward mitochondria. Through the example of the diseleno-Re complex, we showed that the main target could be the oxidative status, with a down-stream regulation of signaling pathways, and further on selective cell death of cancer cells versus normal cells.
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