Norspermidine and novel Pd(II) and Pt(II) polynuclear complexes of norspermidine as potential antineoplastic agents against breast cancer.

Abstract

BACKGROUND: New strategies are needed for breast cancer treatment and one initial step is to test new chemotherapeutic drugs in breast cancer cell lines, to choose candidates for further studies towards clinical use. METHODOLOGY AND FINDINGS: The cytotoxic effects of a biogenic polyamine analogue - norspermidine - and its trinuclear Pd(II) and Pt(II) complexes - Pd(3)NSpd(2) and Pt(3)NSpd(2), respectively - were investigated in one immortalized normal-like and three breast cancer cell lines. The normal-like MCF-10A cells were least sensitive to the compounds, while growth inhibition and cell death was observed in the cancer cell lines. Norspermidine and its Pd(II) complex were generally shown to have stronger antiproliferative effects than the corresponding Pt(II) complex. Moreover, both norspermidine and the Pd(II) complex reduced the cellular activity of the growth-related enzyme, ornithine decarboxylase (ODC) to a lower level than the Pt(II) complex in most of the cell lines examined. Treatment with norspermidine or the Pd(II) complex reduced the number of colonies formed in a soft agar assay performed with the breast cancer cell lines, indicating that these compounds reduced the malignancy of the breast cancer cells. The effect of norspermidine or the Pd(II) complex on colony formation was much stronger than that observed for the Pt(II) complex. The results from a new mammalian genotoxicity screen together with those of a single cell gel electrophoresis assay indicated that none of the drugs were genotoxic at a 25 µM concentration. MAIN CONCLUSIONS: Overall, norspermidine and its Pd(II) complex were shown to have strong antiproliferative effects. In comparison, the effects obtained with the Pd(II) complex were much stronger than that of the Pt(II) complex. The results obtained in the present study demonstrate that the trinuclear Pd(II) complex of norspermidine (Pd(3)NSpd(2)) may be regarded as a potential new metal-based drug against breast cancer, coupling a significant efficiency to a low toxicity.