At present, cisplatin is one of the most widely employed anticancer drugs. Anyway, despite its high effectiveness, the therapy is severely hindered by some clinical problems, such as a severe normal tissues toxicity and the frequent occurrence of either initial or acquired resistance to the treatment. Recently, the research team has designed some gold(III)-dithiocarbamato derivatives which were proved to be much more than cisplatin towards different kind of tumours. These gold(III) complexes were proved to be highly reactive toward some biologically-relevant macromolecules. In particular, the research team has showed that the inhibition of the proteasomal activity by gold(III) dithiocarbamates is a strong apoptotic stimulus in the highly metastatic MDA-MB-231 breast cancer cell cultures and tumors. Moreover, treatment of MDA-MB-231 tumor-bearing nude mice with a gold compound resulted in a significant inhibition of tumor growth, together with lack of systemic toxicity, weight loss, decreased activity, or anorexia. At present, cellular uptake of therapeutic agents is still a challenging task because of the plasma membrane, which constitutes an impermeable barrier for most of these molecules. In order to circumvent this issue, much attention has been recently given to the use of peptide-based delivery systems. Two peptide transporters have been identified in mammals, which are over-expressed in some types of tumors. A unique feature is their capability for sequence-independent transport inside the cells of all possible di- and tripeptides, including differently charged species. On the basis of these considerations, the rationale of research team's strategy was to design gold(III)-peptidodithiocarbamato complexes that can be able to maintain both the antitumor properties and the lack of nephrotoxicity of the previously reported gold(III) analogues, together with an enhanced bioavailability through the di-/tripeptide-mediated cellular internalization by exploiting peptide transporters PEPT1 and PEPT2.

Exposure of PC3 cells (human prostate carcinoma) to increasing concentrations of some of these innovative complexes resulted in a remarkable dose-dependent growth inhibition with IC50 values lower than the reference drug cisplatin. The growth-inhibitory effect on estrogen receptor a-negative human breast cancer MDA-MB-231 cells has been also evaluated. The results suggest that the compounds are very potent in inhibiting human breast cancer MDA-MB-231 cell growth as the previously investigated gold(III)-dithiocarbamato analogues.; they inhibit the proteasomal chymotrypsin-like activity of both purified rabbit 20S proteasome and MDA-MB-231 whole cell extract in a concentration-dependent way resulting, again, two-fold more potent than the previously investigated gold(III)-dithiocarbamato analogues. Further biological studies have been preliminarily showing that the investigated gold(III) complexes induce accumulation of proteasome target proteins, such as Bax and p27, indicating that proteasome inhibition (associated with cell death) is functional and that the proteasome is a major cellular target.

Results obtained on the capability of gold(III)-peptidodithiocarbamato complexes to inhibit the growth of human breast cancer (MDA-MB-231) xenografts in vivo show a significant tumor growth inhibition. After 13 days, control tumors grew to an average size of 453 mm3, whereas in tumor-bearing mice treated with our compound tumors grew to a much smaller average size, corresponding to >90% inhibition.

Taking into account the potential advantages in terms of noticeable in vitro and in vivo antitumor activity, lack of cross-resistance with cisplatin and reduced adverse side-effects (i.e. negligible nephrotoxicity and very low acute toxicity), this kind of gold(III)-dithiocarbamato derivatives may be regarded as prospective metal-based anticancer drugs.

Innovative Aspects:
The gold(III)-peptidodithiocarbamato complexes are very innovative because these new drugs are quite easy to obtain, have an high stability and show a relevant in vitro and in vivo antitumor activity. Furthermore they are generally well tolerated with a very low systemic toxicity. Moreover they have an enhanced bioavailability through the di-/tripeptide-mediated cellular internalization by exploiting peptide transporters which represent an excellent target for the delivery of pharmacologically-active compounds

 

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