Inhibition of cancer cell growth by ruthenium complexes.

BACKGROUND: Previous studies suggest that certain transition metal complexes, such as cisplatin, are efficacious for treating various cancer types, including ovarian, lung, and breast. METHODS: In order to further evaluate ruthenium (Ru) complexes as potential anti-cancer agents, we synthesized and evaluated Ru-arene complexes. Two complexes with the general formula [Ru (η (6)-p-cym) (N-N) Cl](+) were tested for their abilities to inhibit cancer cells. RESULTS: The complex with o-phenylenediamine as the N-N ligand (o-PDA) significantly inhibited growth of breast (MDA-MB-231, MCF-7, SKBR-3, and SUM149), lymphoma (Raji), melanoma (Bowes), and osteosarcoma (HT1080); however, the complex with o-benzoquinonediimine (o-BQDI) was ineffective except for SUM149. In contrast, o-PDA failed to inhibit growth of human breast epithelial cells, MCF-10A. Treatment of MDA-MBA-231 cells with o-PDA resulted in a significant reduction of productions of PDGF-AA, GM-CSF, and VEGF-A proteins at the transcriptional levels. Finally, we demonstrated that o-PDA synergistically inhibited MDA-MB-231 cell growth with cyclophosphamide but not doxorubicin or paclitaxel. CONCLUSION: These results suggest that Ru-arene complexes are promising anti-cancer drugs that inhibit progression and metastasis by blocking multiple processes for breast and other types of cancer.

Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth.

There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the mechanisms of NEDD9-mediated cancer migration and growth, stable cells overexpressing NEDD9 were generated using HCC38 as a parental cell line which expresses low level of endogenous NEDD9. Microarray studies demonstrated that core proteins of CD44 and Serglycin were markedly upregulated in HCC38(NEDD9) cells compared to HCC38(Vector) cells, while those of Syndecan-1, Syndecan-2, and Versican were downregulated in HCC38(NEDD9). Importantly, enzymes generating chondroitin sulfate glycosaminoglycans (CS) such as CHST11, CHST15, and CSGALNACT1 were upregulated in HCC38(NEDD9) compared to HCC38(Vector). Immunofluorescence studies using specific antibody, GD3G7, confirmed the enhanced expression of CS-E subunit in HCC38(NEDD9). Immunoprecipitation and western blotting analysis demonstrated that CS-E was attached to CD44 core protein. We demonstrated that removing CS by chondroitinase ABC significantly inhibited anchorage-independent colony formation of HCC38(NEDD9) in methylcellulose. Importantly, the fact that GD3G7 significantly inhibited colony formation of HCC38(NEDD9) cells suggests that CS-E subunit plays a key role in this process. Furthermore, treatment of HCC38(NEDD9) cells with chondroitinase ABC or GD3G7 significantly inhibited mammosphere formation. Exogenous addition of CS-E enhanced colony formation and mammosphere formation of HCC38 parental and HCC38(Vector) cells. These results suggest that NEDD9 regulates the synthesis and expression of tumor associated glycocalyx structures including CS-E, which plays a key role in promoting and regulating breast cancer progression and metastasis and possibly stem cell phenotypes.

Latin American Agricultural Workers' Job Demands and Resources and the Association With Health Behaviors at Work and Overall Health.

In the present study, we describe the job demands and job resources (JD-R) experienced by agricultural workers in three Latin American countries and their relationship to proactive health behaviors at work and overall health. Following previous research on the JD-R model, we hypothesized that job demands (H1) would be negatively related to agricultural workers' self-reported overall health. On the other hand, we hypothesized that job resources (H2) would be positively related to agricultural workers' overall health. Furthermore, we hypothesized (H3) that workers' engagement in jobsite health promotion practices via their proactive health behaviors at work would partially mediate the relationship between workers' job resources and job demands and overall health. We also had a research question (R1) about whether there were differences by type of job held. The sample of workers who participated in this study (N = 1,861) worked in Mexico, Guatemala, and Nicaragua for one large agribusiness that produces sugar cane. They worked in two distinct areas: company administration and agricultural operations. We administered employee health and safety culture surveys using survey methods tailored to meet the needs of both types of workers. Stratified path analysis models were used to test study hypotheses. In general, we found support for hypotheses 1 and 2. For example, operations workers reported more physically demanding jobs and administrative workers reported more work-related stress. Regardless, the existence of high job demands was associated with poorer overall health amongst both types of workers. We found that workers in more health-supportive work environments perform more proactive health behaviors at work, regardless of their role within the organization. However, hypothesis 3 was not supported as proactive health behaviors at work was not associated with overall health. We discuss future research needs in terms of evaluating these hypotheses amongst workers employed by small- and medium-sized agribusinesses as well as those in the informal economy in Latin America. We also discuss important implications for agribusinesses seeking to develop health promotion programs that meet the needs of all workers.

International Total Worker Health: Applicability to Agribusiness in Latin America.

Total Worker Health® (TWH) is a framework for integrating worker and workplace safety, health, and well-being, which has achieved success in European and US settings. However, the framework has not been implemented in Latin America or in agricultural sectors, leaving large and vulnerable populations underrepresented in the implementation and evaluation of these strategies to improve safety and promote health and well-being. This study presents a case study of how a TWH approach can be applied to a multinational Latin American agribusiness. We describe the process and adaptation strategy for conducting a TWH assessment at multiple organizational levels and in multiple countries. We follow this with a description of a TWH leadership training that was conducted based on the results of the assessment. Finally, we describe our methods to make corporate recommendations for TWH policies and programs that were informed by the TWH assessment and leadership trainings. With this case study we aim to demonstrate the importance and feasibility of conducting TWH in Latin America.

DNA aptamers against exon v10 of CD44 inhibit breast cancer cell migration.

CD44 adhesion molecules are expressed in many breast cancer cells and have been demonstrated to play a key role in regulating malignant phenotypes such as growth, migration, and invasion. CD44 is an integral transmembrane protein encoded by a single 20-exon gene. The diversity of the biological functions of CD44 is the result of the various splicing variants of these exons. Previous studies suggest that exon v10 of CD44 plays a key role in promoting cancer invasion and metastasis, however, the molecular mechanisms are not clear. Given the fact that exon v10 is in the ectodomain of CD44, we hypothesized that CD44 forms a molecular complex with other cell surface molecules through exon v10 in order to promote migration of breast cancer cells. In order to test this hypothesis, we selected DNA aptamers that specifically bound to CD44 exon v10 using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). We selected aptamers that inhibited migration of breast cancer cells. Co-immunoprecipitation studies demonstrated that EphA2 was co-precipitated with CD44. Pull-down studies demonstrated that recombinant CD44 exon v10 bound to EphA2 and more importantly aptamers that inhibited migration also prevented the binding of EphA2 to exon v10. These results suggest that CD44 forms a molecular complex with EphA2 on the breast cancer cell surface and this complex plays a key role in enhancing breast cancer migration. These results provide insight not only for characterizing mechanisms of breast cancer migration but also for developing target-specific therapy for breast cancers and possibly other cancer types expressing CD44 exon v10.

FH535 inhibited migration and growth of breast cancer cells.

There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with ß1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.