Molecular Studies On The Anti-Tumor Effects Of Metal-Based Complexes: Involvement Of The Ubiquitin-Proteasome And Apoptotic Pathways

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use. The discovery more than twenty years ago that the heme-synthesis enzyme ä-aminolevulinic acid dehydratase (ALAD) possesses proteasome inhibitory activity revealed another potential approach for targeting the UPP in cancer. However, this discovery predated the initial investigation into proteasome inhibition as a therapeutic strategy, so a surprising lack of research into the relationship between ALAD and the proteasome exists. Therefore, further investigation into this relationship is necessary. Taken together, these observations validate the proteasome as a viable chemotherapeutic target. Additionally, novel agents that target not only the proteasomal core, but also other factors involved in the pathway, including E3s like XIAP which are also critical components of the apoptotic cascade, as well as potential endogenous inhibitors like ALAD. The data presented in this dissertation suggest a novel interaction between the 20S proteasomal core and ALAD, which results in proteasome inhibition and tumor cell growth suppression, suggesting that targeting this relationship is a promising approach for cancer treatment. Additionally, a series of new metal-based complexes with various metal centers, including cobalt, gold, gallium and the copper chelator nitroxoline were shown to be potent inhibitors of the proteasome in several cancer cell lines and tumor xenograft models. Furthermore, proteasome inhibition was also revealed as a secondary mechanism of cell death for mercury-containing species. Finally, zinc chelation was explored as a strategy for inducing apoptosis via degradation of the E3 ligase X-linked inhibitor of apoptosis (XIAP). Collectively, these data confirm the potential of the UPP as an anticancer target and substantiate several factors within the pathway as viable druggable targets

Use of proteasome inhibitors in anticancer therapy

The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (-)-EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers

Gold(III)-Dithiocarbamato Peptidomimetics in the Forefront of the Targeted Anticancer Therapy: Preclinical Studies against Human Breast Neoplasia

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kgSUP−1 dSUP−1, compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials

Examining the Factor Structure of the Home Mathematics Environment to Delineate Its Role in Predicting Preschool Numeracy, Mathematical Language, and Spatial Skills

A growing body of evidence suggests that the ways in which parents and preschool children interact in terms of home-based mathematics activities (i.e., the home mathematics environment; HME) is related to children’s mathematics development (e.g., primarily numeracy skills and spatial skills); however, this body of evidence is mixed with some research supporting the relation and others finding null effects. Importantly, few studies have explicitly examined the factor structure of the HME and contrasted multiple hypothesized models. To develop more precise models of how the HME supports children’s mathematics development, the structure of the HME needs to be examined and linked to mathematics performance. The purpose of this study was to extend prior work by replicating the factor structure of the HME (as one general HME factor and three specific factors of direct numeracy, indirect numeracy, and spatial) and using those factors to predict direct assessments of children’s numeracy, mathematical language, and spatial skills. It was hypothesized that the general HME factor would be related to each direct assessment, the direct numeracy factor would be related to both numeracy and mathematical language, and the spatial factor would be related to spatial skills. Using a sample of 129 preschool children (M age = 4.71 years, SD = 0.55; 46.5% female), a series of confirmatory factor analyses were conducted. Results diverged somewhat from prior work as the best fitting model was a bifactor model with a general HME factor and two specific factors (one that combined direct and indirect numeracy activities and another of spatial activities) rather than three specific factors as had previously been found. Further, structural equation modeling analyses suggested that, in contrast to expectations, only the direct + indirect numeracy factor was a significant predictor of direct child assessments when accounting for age, sex, and parental education. These findings provide evidence that a bifactor model is important in understanding the structure of the HME, but only one specific factor is related to children’s outcomes. Delineating the structure of the HME, and how specific facets of the HME relate to children’s mathematics skills, provides a strong foundation for understanding and enhancing the mechanisms that support mathematics development

Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44

Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein

Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44

Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44.Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein.Celine Pinheiro received a Ph.D. fellowship from the Portuguese Science and Technology Foundation (SFRH/BD/27465/2006). The authors acknowledge NCI (National Cancer Institute) Tumour Repository MTA, MD, USA for the multitumour tissue microarray (TARP)

Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44

Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein

Cooperation and achievement in preschoolers

According to recent research, children’s learning related skills, such as cooperation, self-regulation, responsibility, and independence, are closely related to their academic outcomes (McClelland, Acock, Morrison 2006). While self regulation during preschool and it’s related skills are predictors of later academic achievement, it might be beneficial to determine a simple screening tool that would identify children who might need to be assessed more in-depth to determine if they would benefit from interventions. Specifically, cooperation with peers is an easily observable behavior, and a predictor of achievement (Ladd, Birtch, and Buhs, 1999), which can be measured with the Observed Child Engagement Scale (Rimm-Kaufman, Curby, Grimm, Nathanson, and Brock, 2009). Scores for preschoolers’ peer cooperation in on the OCES have been found to be related to scores on a self-regulation measure, the Head Toes Knees Shoulders (HTKS) task. Additionally, performance on the HTKS task can be predictive of later academic performance (Ponitz, McClelland, Matthews, and Morrison, 2009). Given the close nature of these relationships, it might be beneficial to further explore the connections between cooperation and achievement. This study attempts to determine those connections by exploring the relationship between observed instances of cooperation with peers as scored on the OCES and academic achievement scores on the Woodcock-Johnson Psychoeducational Battery III Tests of Achievement Applied Problems and Letter-Word Identification subscales (Woodcock and Mather, 2000). The study investigates the following question: (1) What is the relationship between instances of observed cooperation with peers on the OCES and scores Woodcock-Johnson III achievement tasks

Parental marital status and child self-regulation

Parents play an essential role in their child’s development of the skills needed for self-regulation. The current study examined the relationship between parental marital status and child self-regulation. Analyzing a sample of 328 preschool children, results indicate having married parents is related to higher self-regulation in children. These results suggest that living in a single-parent or married parent househol

Examining the Validity of Behavioral Self-Regulation Tools in Predicting Preschoolers' Academic Achievement

The current study investigated the predictive utility among teacher-rated, observed, and directly assessed behavioral self-regulation skills to academic achievement in preschoolers. Specifically, this study compared how a teacher report, the Child Behavior Rating Scale, an observer report, the Observed Child Engagement Scale, and a direct assessment, the Head-Toes-Knees-Shoulders task, relate to early math and literacy skills. The sample consisted of 247 children from 31 preschool classrooms. Trained research assistants observed a subsample of 104 children. Results indicated significant, positive relationships for teacher-rated and directly assessed behavioral self-regulation for early math and literacy skills. Teacher ratings were the strongest predictors of literacy, and the direct assessment emerged as the strongest predictor of math. Observed behavioral self-regulation was not significantly related to either academic domain. Discussion focuses on domain specificity of behavioral self-regulation assessments and the importance of utilizing multiple measurement tools when assessing behavioral self-regulation and relations to early achievement.Keywords: behavioral self-regulation, measurement, academic achievemen