Abstract
Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N 1,N 11-bis(ethyl)norspermine (BENSpm) and N 1-cyclo-propylmethyl-N 11-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd2BENSpm (Pd-BENSpm), Pt2CPENSpm (Pt-CPENSpm) and Pd2Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced cytotoxicity, which might be explained by differences in the cellular uptake of Pd-BENSpm and Pt-CPENSpm. BENSpm and Pd-BENSpm treatment reduced the CD44+CD24− putative cancer stem cell population, evaluated by flow cytometry. Furthermore, Pd-BENSpm was the most efficient compound regarding induction of DNA damage and decrease in colony formation in soft agar. Pt-CPENSpm and Pd-Spm, on the other hand, were shown to be the least toxic compounds of all tested. Pd-Spm efficiently reduced the cellular glutathione levels, which probably was a consequence of its metabolic inactivation by conjugation to this endogenous thiol. The normal-like cells were found to be less sensitive to the agents than the breast cancer cells. Our findings show that Pd-BENSpm exhibits promising anticancer effects which render it suitable for further optimization to develop a new metal-based chemotherapeutic drug for breast cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-013-1621-y) contains supplementary material, which is available to authorized users.
Highlights
The antiproliferative features of cisplatin, [cis-diamminedichloroplatinum (II)], (cis-Pt(NH3)2Cl2), were discovered in 1965 by Barnett Rosenberg and resulted in the successful use of this compound, as the first metal complex, in the treatment of a wide range of solid tumors (Rosenberg et al 1965)
We have shown that several breast cancer cell lines are highly sensitive to treatment with the Pd(II) chelate of the polyamine analogue norspermidine (NSpd) and that this chelate was more toxic than its Pt(II) counterpart (Silva et al 2013)
We investigate the cytotoxic effects of several Pd(II) and Pt(II) polyamine complexes against two human breast cancer cell lines (JIMT-1 and L56Br-C1) and one immortalized normal-like breast epithelial cell line (MCF-10A): two newly synthesized Pd(II) and Pt(II) chelates Pd2BENSpm (Pd-BENSpm) and Pt2CPENSpm (PtCPENSpm) (Silva et al 2012)—and the complex Pd2Spm (Pd-Spm)
Summary
The antiproliferative features of cisplatin, [cis-diamminedichloroplatinum (II)], (cis-Pt(NH3)2Cl2), were discovered in 1965 by Barnett Rosenberg and resulted in the successful use of this compound, as the first metal complex, in the treatment of a wide range of solid tumors (Rosenberg et al 1965). Platinum (Pt)-based agents are widely used as chemotherapeutic compounds in today’s oncological practice, based on their ability to enter the cell nucleus and covalently bind to DNA, yielding stable adducts (Brabec and Kasparkova 2005; Esteban-Fernandez et al 2010). In the few last years, palladium (Pd)(II) complexes have shown significant antitumor activity against different cancer cell lines, along with fewer off-target effects, as compared to cisplatin (Ulukaya et al 2011)
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