Abstract
BackgroundNew 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 FindingsThe cytotoxic effects of a biogenic polyamine analogue – norspermidine – and its trinuclear Pd(II) and Pt(II) complexes – Pd3NSpd2 and Pt3NSpd2, 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 ConclusionsOverall, 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 (Pd3NSpd2) may be regarded as a potential new metal-based drug against breast cancer, coupling a significant efficiency to a low toxicity.
Highlights
Despite advances in the detection and treatment of breast cancer, this is still one of the most widely spread malignant tumor forms among women [1]
We studied the effects of NSpd, Pd-NSpd or PtNSpd treatment on three human breast cancer cell lines (JIMT-1, L56Br-C1 and MCF-7) and one human immortalized normal-like breast epithelial line (MCF-10A)
As the treatments were shown to affect cell proliferation, we further examined whether there were changes in the cell cycle phase distribution induced by each compound and whether they induced cell death using Flow cytometry (FCM)
Summary
Despite advances in the detection and treatment of breast cancer, this is still one of the most widely spread malignant tumor forms among women [1]. Their diamine precursor putrescine (H2N(CH2)4NH2) are positively charged substances at physiological pH and virtually present in all prokaryotic and eukaryotic cells [4,5,6] Because of their cationic nature, the polyamines can interact with negatively charged molecules within the cell, such as DNA, RNA, proteins and phospholipids, thereby affecting their structure and function [7]. The intracellular polyamine pool is limited, at the lower level, by its requirement for cell survival and proliferation and, at the upper limit, by its cytotoxicity, which may induce cell death [8] Due to their importance in essential cellular functions, there is a strict control of the intracellular levels of polyamines via multiple regulatory mechanisms affecting biosynthesis, catabolism, uptake and excretion [8,9]. 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
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