Biologic Activity of a Dinuclear Pd(II)–Spermine Complex Toward Human Breast Cancer

Abstract

A dinuclear palladium-based complex (Pd 2-Spm) was synthesized and compared with cisplatin (cDDP) on two different human breast cancer cell lines (MCF-7 and MDA-MB-231) as well as toward an untransformed cell line (BJ fibroblasts). The results obtained show that Pd 2-Spm is more effective against the estrogen receptors [ER())] cell line MDA-MB-231, while cDDP displayed better results for the ER(+) MCF-7 cell line. It was shown that, like cDDP, Pd 2-Spm triggers phosphorylation of H2AX, indicating that this compound damages DNA. Apart from DNA, Pd 2-Spm also targets the cytoskeleton having a greater impact on cell morphology than cDDP. Pd 2-Spm and cDDP have opposite antiproliferative activities in the presence of the PI3K inhibitor wortmannin. Furthermore , Pd 2-Spm at an optimized concentration displays a rapid antiproliferative effect as opposed to cDDP, which seems to have a slower kinetics. The results point to a distinct mechanism of action for each of these complexes, which may explain their synergistic action when coadminis-trated. Breast cancer is the most common cancer among women and one of the main causes of death in women in Portugal (1-3). Evolution of human breast cancer is related with cells¢ dependence on ovar-ian estrogens, with the presence (+) or absence ()) of estrogen receptors (ER) being an important marker for the prognosis and choice of therapeutic strategies. Generally, patients suffering from ER(+) breast cancer have better life prospects than those with breast cancer lacking ER expression, which tend to be more aggressive (66-month survival rate) (4). For advanced stages of breast cancer , chemotherapy becomes an important therapeutic option. While cisplatin [cis-diamminedichloroplatinum(II), cis-Pt(NH 3) 2 Cl 2 , cDDP, Figure 1A] is still among the most widely used drugs in cancer chemo-therapy, patients that are treated with cDDP suffer from severe side-effects and, very often, develop resistance mechanisms. These facts urge for the pursuit of improved antitumor agents, displaying lower toxicity coupled to a broader spectrum of activity. Hundreds of new cisplatin-based compounds have been synthesized to date, to overcome cisplatin's harmful side-effects while retaining efficacy. Other inorganic agents, comprising different transition metals, have also been studied (5). Pd(II) complexes are particularly interesting because although structurally similar to Pt(II), their reactivity is fairly distinct. In fact, reactions involving Pd(II) are reported to be about 10 4-10 5 faster than those with Pt(II) (6,7). This increased lability is thought to be the main reason for the biologic inactivity of some Pd(II) agents, namely, cis-diamminedichloropalladium(II) (cis-Pd(NH 3) 2 Cl 2 , cDDPd). However, despite the initial belief that Pd(II) compounds were inactive as antineoplastic agents, many have been synthesized and shown to be not only more active than cisplatin (8-10) but also more effective than their Pt(II) counterparts (11-13). Because it is broadly accepted that one of the main targets...

Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy

“…Following previous biological studies by the authors on the effect of the tested Pt(II) and Pd(II) spermine complexes on the growth and viability of several human cancer cells, [14][15][16]22,26,27,40,41,43,45 including the hormone-unresponsive breast carcinoma currently investigated, a cellular response at the biochemical level is presently sought, through analysis of the vibrational pattern of drug-treated and untreated cells. This multidisciplinary approach aims to link biological response to changes in cellular chemistry and metabolism, thus identifying the spectral markers of drug activity and paving the way for an understanding of the drug mode of action at the molecular level, hopefully helping to predict drug efficacy under specic conditions.…”

“…The data obtained within this work, coupled to conformational analysis of the metal complexes and cytological assays (for evaluation of growth-inhibition, cytotoxic and anti-metastatic activities) previously carried out at QFM-UC, [14][15][16]22,[25][26][27][40][41][42][43][44][45] will pave the way for future studies on other platinum and palladium-based polyamine agents prepared by the authors. This approach should provide valuable clues for the rational design of novel cisplatin-like drugs, displaying a higher efficiency, lower toxicity, decreased acquired resistance and possible oral administration.…”

“…12,13 However, their mechanism of action is not yet fully understood at the molecular level. Furthermore, their Pd(II) analogues have recently arisen as innovative and promising alternatives to Pt(II) compounds, [9][10][11]14,15 particularly against metastatic breast cancer, 16 namely when using strongly coordinating polydentate ligands such as polyamines, which minimise displacement by sulydryl groups from glutathione and other cellular thiols (responsible for drug inactivation and deleterious side effects). 17 A careful design of palladium complexes may thus allow targeting strategies leading to different proles of drug activity and to a lack of cross-resistance as compared with platinum-based agents.…”

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

“…The detailed knowledge of the molecular basis of the cDDP-guanine/adenine and cDDPglutathione interplay gathered in this work will pave the way for future studies on other platinum and palladium-based agents previously characterized by the authors and assessed as to their cytotoxicity towards several human cancer cell lines. [29][30][31][32][33][34][35][36][37] This will provide valuable clues for the rational design of novel cisplatin-like drugs, displaying a higher efficiency, lower toxicity, decreased acquired resistance and possible oral administration. …”

Cardiotoxicity of Palladium Compounds / Kardiotoksičnost Jedinjenja Paladijuma

“…The latest research indicated that some palladium complexes were effective in the treatment of non-small-cell lung cancer (10), breast cancer (11,12) and ovarian cancer (13).…”