Synthesis, Characterization, and Cytotoxicity Evaluation of Novel Water-Soluble Cationic Platinum(II) Organometallic Complexes with Phenanthroline and Imidazolic Ligands.

Platinum-based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water-soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η1-C2H4OEt)(phen)] (1, phen=1,10-phenanthroline) precursor, specifically [Pt(NH3)(η1-C2H4OEt)(phen)]Cl (2), [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl (3), and [Pt(1-hexyl-1H-benzo[d]imidazole)(η1-C2H4OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki-1), and normal human renal cells (HK-2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki-1) among the tested complexes, compared to healthy cells (HK-2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum-based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties.

The impact of adapted exercises in basketball on the perception of the difficulty and physical enjoyment of students with overweight.

The purpose of this study was to investigate the effect of the adapted basketball cycle on the perceived level of difficulty and physical enjoyment in girls and boys with overweight. Sixty-six students with overweight (aged 16-18 years) were randomly assigned to an experimental group (EG, n = 32 including 20 boys and 12 girls) and a control group (CG, n = 34; including 21 boys and 13 girls). Statistical analysis also showed that the levels of perceived difficulty decreased significantly after of seven-week of the adapted basketball cycle in both boys (Δ% = - 0.27; p < 0.001; and girls (Δ% = - 0.36; p < 0.001). There was no significant difference in students who participated in the traditional basketball cycle. A physical activity enjoyment Scale revealed that in girls, the level of enjoyment increased significantly (Δ% = + 0.27; P < 0.001) after an adapted basketball cycle. There was no significant change in physical enjoyment in boys EG (P = 0.808) and participants in the control groups. These results push us to opt more for adapted and motivational learning situations to make the teaching-learning process better, in students with overweight.

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies.

Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes. In the UK and Italy, particular attention should be paid to the Medicines & Healthcare Products Regulatory Agency (MHRA) phase I accreditation scheme and the specific rules set by the Italian Drug Authority through the AIFA Determination no. 809/2015. Both reference documents are based on the concept of quality risk management while conducting phase I clinical studies. Moreover, the AIFA determination outlines specific requirements for those sites that want to conduct non-profit phase I clinical trials. Indeed, the document reports peculiar activities to the "Clinical Trial Quality Team", which is a team that should support the clinical site researchers in designing, starting, performing, and closing non-profit phase I studies. In this paper, we provide a general overview of the main European guidelines concerning the management of risks during phase I trials, focusing on the main peculiarities of the schemes and rules set by the MHRA and AIFA.

Enhancing Time Reading and Recording Skills in First-Grade Children with Learning Difficulties Using the "Clock Motor Game".

This study aimed to explore the effect of the motor game, "Clock Motor Games", on the improvement of "Reading and Recording of Time" (RRT) in children with Grade 1 mathematical learning difficulties (MLDs). A within-school cluster-randomized intervention study was conducted with 232 children (aged 6-7 years) with limited physical education experience (0.7 ± 0.3 years). The participants were divided into two groups: a control group, which received conventional teaching on time without any additional motor activities, and an experimental group, which incorporated the concept of time with the "Clock Motor Game", for 3 weeks. The Clock-Reading Test was administered before the intervention (T0), immediately after each session (T1), and five weeks after the intervention (T2) in both groups. The results demonstrated that the experimental group exhibited significantly greater improvements in RRT performance compared to the control group (U = 4416.5; p < 0.001; r = 0.3; medium effect). Additionally, the experimental group was more likely to show progress and less likely to experience regression or stagnation compared to the control group (25% vs. 38.4%). The findings suggest that practicing "Clock Motor Games" can positively contribute to the RRT ability in children with Grade 1 MLD.

The relationship between emotional intelligence, anxiety, and performance in physical education and sport students.

Emotional intelligence (EI) has been recently the main target in research on sports psychology. The objectives of this study were to investigate the relation between self-report measures of emotional intelligence, pre-competitive anxiety, and performance among students during the physical education exam of the high school final year. This cross-sectional study was conducted on a sample of 350 students attending the physical education exam in the year 2021-2022. Analysis of the correlations between the scores of Emotional intelligence and anxiety showed that self-confidence was positively correlated with all dimensions of Emotional intelligence (Beta = 0.524; p = 0.000). Multivariate linear regression analysis showed that the most related items to performance were self-confidence in a positive direction (r = 0.56; p = 0.000) and negatively with somatic anxiety (r = -0, 39; p = 0.000). Considering the Emotional intelligence subscales, hetero-emotional management was significantly positively associated with performance (p = 0.000) however emotional perception was negatively correlated with performance (p = 0.003). These results demonstrate the importance of social and emotional learning programs for improving self-confidence and better management of emotions during physical education and sports.

Oxidative status alteration during aerobic-dominant mixed and anaerobic-dominant mixed effort in judokas.

This study aimed to depict the oxidative status variation in judokas during aerobic-dominant mixed effort (AeDME) and anaerobic-dominant mixed effort (AnDME). It is to be expected that the sporting commitment of Judo is a stimulus of oxidative stress leading to the recruitment of antioxidant responses. Blood samples were collected from 17 athletes at rest, immediately after a training session (AeDME) and after a 5-min bout (AnDME). AeDME and AnDME caused significant increases in malondialdehyde (MDA) (p < 0.01 and p < 0.001 respectively) and glutathione (GSH) (p = 0.018 and p < 0.001 respectively). Blood thiol concentrations decreased following AeDME and AnDME (p < 0.001) whilst catalase decreased significantly after AnDME (p = 0.026) only. Uric acid increased significantly after AnDME than after AeDME (p = 0.047) while, conversely, total bilirubin was higher after AnDME than after AeDME (p = 0.02). We may ultimately summarize that AeDME and AnDME caused oxidative stress, higher in AnDME, and some antioxidant response slightly higher in AnDME compared to AeDME. In sports, monitoring of oxidative stress status is recommended as part of the training regimen.

Evaluation of the Antitumor Effects of Platinum-Based [Pt(η1-C2H4-OR)(DMSO)(phen)]+ (R = Me, Et) Cationic Organometallic Complexes on Chemoresistant Pancreatic Cancer Cell Lines.

Pancreatic cancer is one of the most lethal malignancies with an increasing incidence and a high mortality rate, due to its rapid progression, invasiveness, and resistance to anticancer therapies. In this work, we evaluated the antiproliferative and antimigratory activities of the two organometallic compounds, [Pt(η1-C2H4-OMe)(DMSO)(phen)]Cl (1) and [Pt(η1-C2H4-OEt)(DMSO)(phen)]Cl (2), on three human pancreatic ductal adenocarcinoma cell lines with different sensitivity to cisplatin (Mia PaCa-2, PANC-1, and YAPC). The two cationic analogues showed superimposable antiproliferative effects on the tested cells, without significant differences depending on alkyl chain length (Me or Et). On the other hand, they demonstrated to be more effective than cisplatin, especially on YAPC cancer cells. For the interesting cytotoxic activity observed on YAPC, further biological assays were performed, on this cancer cell line, to evaluate the apoptotic and antimetastatic properties of the considered platinum compounds (1 and 2). The cytotoxicity of 1 and 2 compounds appeared to be related to their intracellular accumulation, which was much faster than that of cisplatin. Both 1 and 2 compounds significantly induced apoptosis and cell cycle arrest, with a high accumulation of sub-G1 phase cells, compared to cisplatin. Moreover, phenanthroline-containing complexes caused a rapid loss of mitochondria membrane potential, ΔΨM, if compared to cisplatin, probably due to their cationic and lipophilic properties. On 3D tumor spheroids, 1 and 2 significantly reduced migrated area more than cisplatin, confirming an antimetastatic ability.

The Feeling of Pleasure for Overweight Children during Different Types of Physical Activity.

The feeling of pleasure during physical education (PE) could increase with physical activity participation and adherence for overweight children. While traditional games are known to have positive benefits on motor skill development, especially for children with poorer motor skills, and on the body mass of children, little is known about overweight children's feelings of enjoyment when playing these games. To identify a program of physical activity appreciated by overweight children, we tested the effect of different activities, namely soccer (SO), shot put (SP), and traditional motor games (TMGs), on the feelings of pleasure for 28 overweight male children (aged 12.11 ± 0.63 years, BMI 26.89 ± 0.15 kg·m-2) participating in a 3-month cross-over study. To measure affective responses to exercises, we applied a validated feeling scale. The data were collected during eight PE lessons, which were organized for each cycle taught. Post hoc pairwise comparisons revealed a significant difference (Z = -3.195, p < 0.01) between the mean feeling score reported after the SO cycle (2.48 ± 0.41) and that after the TMGs (3.04 ± 0.32). A similar significant difference (Z = -3.304, p < 0.01) was found between the mean feeling scores reported after the SP cycle (2.27 ± 0.32) and the TMGs (3.04 ± 0.32). There was no significant difference between the mean feeling scores reported after the SO (2.48 ± 0.41) and SP cycles (2.27 ± 0.32). In conclusion, the findings of the present study suggest that TMGs may have beneficial effects on the feelings of pleasure for overweight children. Therefore, TMGs might potentially be considered as an alternative to conventional physical activities.

Immunolocalization of the AT-1R Ang II Receptor in Human Kidney Cancer.

This study aimed to evaluate AT1-R expression in normal and cancerous human kidneys, how these expressions are modified, and AT1-R functionality. AT-1R mRNA expression, determined by real-time PCR, was detected in all samples. AT-1R mRNA increased in well-differentiated cancer (G1, p < 0.01) and decreased 2.9-fold in undifferentiated cancer (G4, p < 0.001) compared with normal kidney tissues. Immunocytochemistry analysis showed that the AT-1R was expressed in the normal tubular epithelium. The glomerulus was also immunoreactive, and as expected, the smooth muscle cells of the vessel walls also expressed the receptor. A total of 35 out of 42 tumors were AT-1R positive, with the cell tumors showing varying numbers of immunoreactive cells, which were stained in a diffuse cytoplasmic and membranous pattern. Computer-assisted counting of the stained tumor cells showed that the number of AT-1R-positive cells increased in the well-differentiated cancers. The functionality of AT-1R was assessed in primary cultures of kidney epithelial cells obtained from three G3 kidney cancer tissues and corresponding histologically proven non-malignant tissue adjacent to the tumor. Indeed, Ang II stimulated, in a dose-dependent manner, the 24 h proliferation of normal kidney cells and cancer cells in the primary culture and phosphorylated extracellular regulated kinases 1 and 2. In conclusion, Ang II may be involved in the growth or function of neoplastic kidney tissue.

The effects of adapted physical education sessions on the empathy of female students with overweight.

The global prevalence of childhood and adolescent overweight and obesity increases rapidly. Physical activity plays a major role in the prevention of obesity. The present study aimed to analyze the effect of adapted basketball sessions according to the empathic capacity of adolescent girls with overweight. Forty-two girls with overweight (age: 16.09 ± 0.85; years; height: 1.64 ± 0.67 m: weight: 73.02 ± 0.61 kg; BMI: 27.15 ± 1.37) volunteered to participate in the study and were randomly assigned to the experimental group (EG, n = 21) and control group (CG, n = 21). EG was submitted to a basketball intervention adapted to students with obesity while the CG performed classic basketball exercises for 7 weeks. Each week girls had 2 basketball teaching-learning sessions, lasting 50 min. The participants' empathy was assessed before and after the intervention using the Favre CEC. The results showed that adaptation intervention was associated with a significant emotional contagion decrease (Δ% = 0.466) and splitting with emotions (Δ% = 0.375), and with an empathy increase (Δ% = 1.387), in EG compared to CG. No significant difference was assessed in the empathy CG, before and after the intervention. This study demonstrated that adapted physical education classes could be an effective strategy to improve empathetic skills and inclusion of overweight girls as well as a means to prevent obesity.

Effects on Children's Physical and Mental Well-Being of a Physical-Activity-Based School Intervention Program: A Randomized Study.

This study aimed to evaluate the effectiveness of physically active breaks of a total duration of 10 min a day, introduced during curricular lessons, together with a 10 min physical activity intervention during the daily school recess period on obesity prevention, fitness, cognitive function, and psychological well-being in school-aged children. A sample of 310 children (139 boys vs. 171 girls), aged between 8 and 10 years (9.82 ± 0.51), was selected. Our strategy was implemented over a 6-month period and the participants were randomly assigned to either the intervention group (n = 157) or the non-intervention (control) group (n =153). In the intervention group, a significant decrease (p < 0.05) in body mass index, waist circumference, waist-height ratio, and relative body fat mass was achieved after the intervention (T1) compared to the values measured before intervention (T0); in the control group, no differences emerged between T0 and T1 for any of the parameters considered. We found a significant increase in the intervention group in standing long jump, Ruffier, and sit and reach test scores (p < 0.001 for all). At T0, cognitive test scores did not differ between the girls and boys or between the intervention and control groups; instead at T1, significant differences were observed in the two groups regarding the total number of responses and the concentration performance scores (p < 0.001). Consistently, in the intervention group, well-being levels significantly increased between T0 and T1 (p < 0.001). Finally, the intervention had significant effects on the children regardless of gender. We may therefore conclude that schools should create more opportunities for teachers and students to introduce intervention strategies to promote regular PA during school recess.

Integration of Obese Children in Physical Education Sessions: An Exploratory Study.

We investigated the effect of the role of the joker in children with obesity (OCs) on integration and physio-psychological responses during small-sided games (SSG) training programs. Sixteen OC students (age 13.8 ± 0.73 years) performed training programs consisting of two sessions a week for three weeks. The experimental protocol consisted of 16 teams of 4 children (3 of normal weight and 1 OC). The 16 teams were divided into 2 groups, one with an OC playing as the joker (SSG-J) and the other group with OC playing as non-joker (SSG-NJ). Maximum heart rates (HRmax), blood lactate concentration [La] and OMNI-Child perceived exertion were measured at the end of each SSG. A physical activity enjoyment Scale (PACES) was accomplished during physical activity for the evaluation of feelings in OCs. Additionally, the profile of mood states (POMS) was measured before and after the SSG-J and SSG-NJ programs. HRmax, [La], perceived exertion, and PACES scores were significantly higher after the SSG-J compared with SSG-NJ (increments of 6.4%, 31.7%, 19.5% and 18.1%, respectively). The score of the POMS variables was positively increased in the presence of jokers. The vigor score increased by 30%, while tension and total mood disturbance scores decreased by 27.6% and 4.5%, respectively. These findings suggest that the joker role could be effective in improving integration, physical enjoyment, physiological responses and mood states in OCs when a team game is used during PE sessions. PE teachers could then program joker exercises with the aim of improving OCs' physical commitment willingness to play.

Oxidized Alginate Dopamine Conjugate: A Study to Gain Insight into Cell/Particle Interactions.

Background: We had previously synthetized a macromolecular prodrug consisting of oxidized Alginate and dopamine (AlgOx-Da) for a potential application in Parkinson disease (PD). Methods: In the present work, we aimed at gaining an insight into the interactions occurring between AlgOx-Da and SH-SY5Y neuronal cell lines in view of further studies oriented towards PD treatment. With the scope of ascertaining changes in the external and internal structure of the cells, multiple methodologies were adopted. Firstly, fluorescently labeled AlgOx-Da conjugate was synthetized in the presence of fluorescein 5(6)-isothiocyanate (FITC), providing FITC-AlgOx-Da, which did not alter SH-SY5Y cell viability according to the sulforhodamine B test. Furthermore, the uptake of FITC-AlgOx-Da by the SH-SY5Y cells was studied using scanning near-field optical microscopy and assessments of cell morphology over time were carried out using atomic force microscopy. Results: Notably, the AFM methodology confirmed that no relevant damage occurred to the neuronal cells. Regarding the effects of DA on the intracellular reactive oxygen species (ROS) production, AlgOx-Da reduced them in comparison to free DA, while AlgOx did almost not influence ROS production. Conclusions: these findings seem promising for designing in vivo studies aiming at administering Oxidized Alginate Dopamine Conjugate for PD treatment.

Comparison of the Physical, Physiological, and Psychological Responses of the High-Intensity Interval (HIIT) and Small-Sided Games (SSG) Training Programs in Young Elite Soccer Players.

We investigated the effects of high-intensity interval (HIIT) and small-sided games (SSG) training programs on physiological and psychological responses in young soccer players. Twenty-four male soccer players (age 16.7 ± 0.9 years) were divided into two groups (HIIT and SSG) and completed a 6-week training programs consisting of two training sessions a week. HIIT consisted of intermittent runs lasting 15 s at the 110% maximum aerobic speed followed by a passive recovery lasting 15 s; SSG was instead structured in a 4 versus 4 players games on a playing field of 25 × 35 m. The muscular power of the lower body was assessed before and after each training session using the 5-jump test to leg length, and two incremental field tests (VAMEVAL test and modified agility t-test). Our results show that HIIT and SSG have similar beneficial effects on the variables connected to the soccer-specific performance and the endurance with little influence on neuromuscular performances. Psychological responses were assessed using the "physical activity enjoyment scale", the Hooper index and the POMS variables. Results showed that SSG offers greater perceived enjoyment than what can be achieved with HIIT. In conclusion, SSG can be considered an effective, more motivating, and fun soccer-specific training that brings about physiological responses and neuromuscular adjustments in young soccer players.

Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries.

BACKGROUND: Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies. METHODS: The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.

Efficacy of school-based intervention programs in reducing overweight: A randomized trial.

Childhood obesity represents a serious public health problem and this study evaluates the effectiveness of a 6-month educational intervention on lifestyle, nutrient adequacy, and diet quality in the school setting in improving the knowledge and behavior of primary school children regarding correct eating habits. The strategy was implemented over a 6-month period and participants were randomly assigned to either the intervention group (n = 200) or the non-intervention group (control group, n = 197). Participants had a mean body mass index of 18.3 ± 2.7 kg/m2 and its variation in the intervention group (-2.7 ± 0.5 kg/m2) was significantly different from that in the control group (3.41 ± 0.8 kg/m2). In the experimental group, there were significant differences between the proportion of children who were overweight, underweight, normal weight, or obese before and after intervention (p < 0.05). The best results were seen in the female sex, and after the intervention, there were no more girls with obesity. Furthermore, there were significant waist circumference decrement effects in the intervention group compared to the control group (p < 0.05). Finally, many of the participating children acquired healthy eating habits. Therefore, the quantitative results obtained suggest that a school intervention program represents an effective strategy to prevent and improve the problem of childhood overweight and obesity.

Mental Fatigue Effects on the Produced Perception of Effort and Its Impact on Subsequent Physical Performances.

The purpose of this study was to investigate the relationship between mental fatigue induced by a demanding cognitive task and impaired physical performance in endurance due to a higher perception of effort. A total of 12 healthy adults and volunteers, who had previously practiced endurance activities for 4 to 8 h per week, performed a one-hour cognitive task involving either the process of response inhibition (Stroop task) or not (visualization of a documentary as control task), then 20 min of pedaling on a cycle ergometer at a constant perception of effort while cardio-respiratory and neuromuscular functions were measured. The Stroop task induces subjective feelings of mental fatigue (vigor: 3.92 ± 2.61; subjective workload: 58.61 ± 14.57) compared to the control task (vigor: 5.67 ± 3.26; p = 0.04; subjective workload: 32.5 ± 10.1; p = 0.005). This fatigue did not act on the produced perceived effort, self-imposed, and did not affect the cardio-respiratory or neuromuscular functions during the subsequent physical task whose type was medium-term endurance. Regardless of the mental condition, the intensity of physical effort is better controlled when the participants in physical activity control their perception of effort. Mental fatigue does not affect subsequent physical performance but estimated perceived exertion, which increases with the intensity and duration of the exercise.

Monitoring Psychometric States of Recovery to Improve Performance in Soccer Players: A Brief Review.

In order to maximize adaptations and to avoid nonfunctional overreaching syndrome or noncontact injury, coaches in high-performance sports must regularly monitor recovery before and after competitions/important training sessions and maintain well-being status. Therefore, quantifying and evaluating psychometric states of recovery during the season in sports teams such as soccer is important. Over the last years, there has been substantial growth in research related to psychometric states of recovery in soccer. The increase in research on this topic is coincident with the increase in popularity obtained by subjective monitoring of the pre-fatigue state of the players before each training sessions or match with a strong emphasis on the effects of well-being or recovery state. Among the subjective methods for players' control, the Hooper index (HI) assesses the quality of sleep during the previous night, overall stress, fatigue, and delayed-onset muscle soreness. Additionally, the total quality of recovery (TQR) scale measures recovery status. The HI and TQR recorded before each training session or match were affected by the variability of training load (TL) and influenced the physical and technical performances, and the affective aspects of soccer players. Researchers have recommended wellness monitoring soccer players' psychometric state of recovery before each training session or match in order to detect early signs of fatigue and optimize high-level training performance. This method allows for better detecting signs of individual fatigue and allows coaches to adapt and readjust the TL, and avoid physical and technical gaps in order to improve the performance of soccer players.

Antitumor and antimigration effects of a new Pt compound on neuroblastoma cells.

Among the new Pt complexes with anticancer properties, phenanthroline derivatives have aroused great interest due to their different mode of action compared to cisplatin. We previously examined cytotoxic effects of a new Pt(II)-complex containing 1,10-phenantroline (phen), [Pt(η1-C2H4OMe)(DMSO)(phen)]Cl, in a panel of eight human cancer cell lines, and showed that it exerted the greatest cytotoxic effect in the neuroblastoma SH-SY5Y cell line. In this study, the antiproliferative and antimetastatic potential of [Pt(η1-C2H4OMe)(DMSO)(phen)]+ (in short Pt-EtOMeSOphen) was investigated in neuroblastoma SH-SY5Y, SK-N-SH and SK-N-BE(2) cells. Pt-EtOMeSOphen provoked the early signs of apoptosis induction (cleavage of PARP and activation of caspases-9 and -7); it also increased the level of proapoptotic Bax protein whereas it decreased the level of the antiapoptotic Bcl-2 protein. The effects of Pt-EtOMeSOphen on migration and invasion processes were also evaluated. A decrease of cell migration/invasion by Pt-EtOMeSOphen was observed through 2D and 3D in vitro assays. Pt-EtOMeSOphen was found to exert its actions by decreasing MMP-9 and MMP-2 expressions and activities. Pt-EtOMeSOphen provoked the phosphorylation of both ERK1/2 and p38 MAPKs. All the effects of Pt-EtOMeSOphen on SH-SY5Y cell vitality, migration and metalloproteases activities described here were due to the activation of p38 MAPK since pharmacological p38 MAPK inhibition or small interfering RNAs to p38 MAPK mRNA blocked such effects. Results suggest that Pt-EtOMeSOphen inhibits neuroblastoma cancer cells survival, motility, and invasion. This could lead to the reduction of neuroblastoma metastatic potential.

A NMR-Based Metabolomic Approach to Investigate the Antitumor Effects of the Novel [Pt(η 1-C2H4OMe)(DMSO)(phen)]+ (phen = 1,10-Phenanthroline) Compound on Neuroblastoma Cancer Cells.

NMR-based metabolomics is a very effective tool to assess the tumor response to drugs by providing insights for their mode of action. Recently, a novel Pt(II) complex, [Pt(ƞ1-C2H4OMe)(DMSO)(phen)]+ (phen = 1,10-phenanthroline), Pt-EtOMeSOphen, was synthesized and studied for its antitumor activity against eight human cancer cell lines. Pt-EtOMeSOphen showed higher cytotoxic effects than cisplatin in most of the cancer cell lines and in particular against the neuroblastoma cell line (SH-SY5Y). In this study, the mechanism of action of Pt-EtOMeSOphen on SH-SY5Y cells was investigated using 1H NMR-based metabolomics and compared with cisplatin. The observed time response of SH-SY5Y cells under treatment revealed a faster action of Pt-EtOMeSOphen compared with cisplatin, with a response already observed after six hours of exposure, suggesting a cytosolic target. NMR-based metabolomics demonstrated a peculiar alteration of the glutathione metabolism pathway and the diacylglycerol expression.