Cancer, one of the major causes of death across the world, has shown to be a largely preventable disease, highly susceptible to modulation by dietary factors. Phenolic compounds, abundant in vegetables and fruits ubiquitous in diet, were described to play an important role as chemopreventive agents. Since conventional therapeutic and surgical approaches have not been able to control the incidence of most cancer types, the development of chemopreventive strategies is an urgent priority in public health. The current diet phenolic intake is often insufficient to protect from mutagens (either exogenous or endogenous), which leads to the need for dietary supplementation as an alternative approach. Research efforts are placing increasing emphasis on identifying the biological mechanisms and in particular the signal transduction pathways related to the chemopreventive activities of these compounds. These effects are believed to occur by the regulation of signaling pathways such as nuclear factor-kB (NF-kB), activator protein-1 (AP-1) or mitogen-activated protein kinases (MAPK). Dietary polyphenols can exert their effects on these pathways separately or sequentially and in addition the occurrence of crosstalk between these pathways cannot be overlooked. By modulating cell signaling pathways, polyphenols activate cell death signals and induce apoptosis in precancerous or malignant cells resulting in the inhibition of cancer development or progression. However, regulation of cell signaling pathways by dietary polyphenols can also lead to cell proliferation/survival or inflammatory responses due to increased expression of several genes. The present review summarizes the most recent advances providing new insights into the molecular mechanisms underlying the promising anticarcinogenic activity of dietary polyphenols. ß

Several phenolic acids-caffeic and gallic acid derivatives-were synthesized and screened for their potential antiproliferative and cytotoxic properties, in different human cancer cell lines: mammary gland and cervix adenocarcinomas and lymphoblastic leukemia. The selected phenols were structurally related, which allowed us to gather important information regarding the structure-activity relationships underlying the biological activity of such compounds. This is proposed to be due to a balance between the antioxidant and pro-oxidant properties of this kind of agent. Distinct effects were found for different cell lines, which points to a significant specificity of action of the drugs tested. It was verified, for the types of cancer investigated, that the trihydroxylated derivatives yielded better results than the dihydroxylated ones. Tests in noncancerous cells, human lung fibroblasts, were also undertaken, in view of determining the toxic side effects of the compounds studied.

A conformational and vibrational analysis of cisplatin ͓cis-diamminedichloro-platinum͑II͔͒ ͑cDDP͒ is reported. Several theory methods ͑from Hartree-Fock to Møller-Plesset and density functional theory͒ combined with different all-electron basis sets are evaluated, in view of determining the best suited strategy for accurately representing this molecule. This choice is based on the best compromise between accuracy and computational requirements. Different scaling models of the cDDP vibrational modes were tested for obtaining the best scaling factors to be used in this type of inorganic systems. The structural parameters and vibrational results predicted by the calculations are compared with the corresponding experimental data, namely, x-ray structure, and Raman and inelastic neutron scattering spectra. Finally, a complete assignment of the cDDP vibrational spectra is presented.

Polyamines are small cationic molecules required for cellular proliferation and are detected at higher concentrations in most tumour tissues, compared to normal tissues. Agmatine (AGM), a biogenic amine, is able to arrest proliferation in cell lines by depleting intracellular polyamine levels. It enters mammalian cells via the polyamine transport system. Agmatine is able to induce oxidative stress in mitochondria at low concentrations (10 or 100 lM), while at higher concentrations (e.g. 1-2 mM) it does not affect mitochondrial respiration and is ineffective in inducing any oxidative stress. As this effect is strictly correlated with the mitochondrial permeability transition induction and the triggering of the pro-apoptotic pathway, AGM may be considered as a regulator of this type of cell death. Furthermore, polyamine transport is positively correlated with the rate of cellular proliferation. By increasing the expression of antizyme, a protein that inhibits polyamine biosynthesis and transport, AGM also exhibits a regulatory effect on cell proliferation. Methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase, displaying anticancer activity, is a structural analogue of the natural polyamine spermidine. MGBG has been extensively studied, preclinically as well as clinically, and its anticancer activity has been attributed to the inhibition of polyamine biosynthesis and also to its effect on mitochondrial function. Numerous findings have suggested that MGBG might be used as a chemotherapeutic agent against cancer.

The antiproliferative and cytotoxic properties of polyphenolic acid derivatives, structurally related with the natural models caffeic and gallic acids, have been tested in human cervix adenocarcinoma cells (HeLa). Simultaneous structural information was obtained for these compounds through theoretical ab initio methods. This study was conducted for the following esters: methyl caffeate (MC, 1), propyl caffeate (PC, 2), octyl caffeate (OC, 3), methyl gallate (MG, 4), propyl gallate (PG, 5) and octyl gallate (OG, 6). A significant growth-inhibition effect was assessed for some of these compounds, clearly dependent on their structural characteristics. Marked structure-activity relationships (SARs)--namely the number of hydroxyl ring substituents--were found to rule the biological effect of such systems.

Aberrantly regulated apoptosis is involved in the pathogenesis of several diseases and defective apoptosis leads to uncontrolled cell proliferation and tumorigenesis. Cancer is an example of a pathologic condition where the normal mechanisms of cell cycle regulation are dysfunctional either by excessive cell proliferation, inhibited/suppressed apoptosis or both. Dietary habits are estimated to contribute to, at least, one third of all human cancers, showing that dietary components can exacerbate or interfere with carcinogenesis. However, several epidemiological studies have revealed that some dietary factors can decrease the risk of different types of cancer. Apoptosis is suggested to be a crucial mechanism for the chemopreventive properties associated with several dietary factors by eliminating potentially deleterious (damaged/mutated) cells. Food, a readily available item, contains several promising chemopreventive agents. Polyphenols are serious candidates since they are responsible for the cancer protective properties of a diet rich in vegetables and fruits: numerous phenolic compounds showed antiproliferative and cytotoxic effects and, more specifically, pro-apoptotic activities, in several cancer cells lines and animal tumor models. The aim of the present review is to analyze and summarize several aspects related to the molecular mechanisms of apoptosis induced by dietary factors with particular emphasis on polyphenols. Dietary factors that can activate cell death signals and induce apoptosis, preferentially in precancerous or malignant cells, and the study of their apoptotic inducing targets can represent a mean to devise new strategies for cancer prevention in the future.

The first neutron scattering study on human nucleated cells is reported, addressing the subject of solvent-slaving to a drug by probing intracellular water upon drug exposure. Inelastic and quasi-elastic neutron scattering spectroscopy with isotope labelling was applied for monitoring interfacial water response to the anticancer drug cisplatin, in the low prognosis human metastatic breast cancer cells MDA-MB-231. Optical vibrational data were also obtained for lyophilised cells. Concentration-dependent dynamical changes evidencing a progressive mobility reduction were unveiled between untreated and cisplatin-exposed samples, concurrent with variations in the native organisation of water molecules within the intracellular medium as a consequence of drug action. The results thus obtained yielded a clear picture of the intracellular water response to cisplatin and constitute the first reported experimental proof of a drug impact on the cytomatrix by neutron techniques. This is an innovative way of tackling a drug's pharmacodynamics, searching for alternative targets of drug action.

Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level.This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(II) and Pd(II) dinuclear chelates with spermine (Pt 2 Spm and Pd 2 Spm), using cisplatin (cis-Pt(NH 3 ) 2 Cl 2 ) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 mM) at 48 h exposure.Multivariate data analysis was applied (unsupervised PCA), unveiling drug-and concentration-dependent effects: apart from discrimination between control and drugtreated cells, a clear separation was obtained for the different agents studiedmononuclear vs. polynuclear, and Pt(II) vs. Pd(II). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(II) agent having a more significant impact on proteins while its Pt(II) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents.