New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.

Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets. Here, we discuss the scientific rationale for miRNA-based therapeutics in B cell neoplasias and review recent advances that may help establish a basis for novel candidate miRNA-based therapies for B cell-NHL (B-NHL). miRNA-Based Therapies in B-NHLLymphomas arise from the neoplastic transformation of either T or B lymphocytes. About 95% of all human lymphomas originate in B cells, rather than T cells, and most of them (75-85%) arise from mature B cells that are germinal center (GC, see Glossary) experienced [1]. GCs are unique structures in which Ig genes are remodeled and are thus essential for the generation of high-affinity antibodies required for a proficient immune response. The production of highaffinity antibodies entails the introduction of mutations and DNA double-strand breaks in Ig genes and thus increases the risk of generating oncogenic events in mature B cells that transit through the GC [2,3]. Mature B cell neoplasia underlies the vast majority of lymphocyte-derived cancers, including most B-NHLs, such as diffuse large B cell lymphomas (DLBCLs), follicular lymphoma (FL), Burkitt lymphoma (BL), multiple myeloma (MM), and B cell chronic lymphocytic leukemia (CLL) [4]. It is estimated that B-NHL affects 1.3 million people worldwide [Global Cancer Observatory (GCO), World Health Organization i ].While some types of B-NHL progress relatively slowly and are considered indolent cancers, about 60% of them, including BL and DLBCL, are aggressive and require immediate intervention [1]. In general, the main treatments for mature B-NHL are chemotherapy, immunochemotherapy, and radiation therapy; however, a significant fraction of these cancers are refractory to these interventions or relapse after treatment [1,5]. There is therefore an urgent need for alternative therapeutic strategies to replace or complement current approaches. Advances in knowledge of the molecular mechanisms underlying lymphomagenesis have led to the design of promising new drugs that target specific genes and proteins involved in neoplasia development or maintenance. Clinically available strategies targeting B-NHL currently include: (i) immunotherapy with celldirected monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapy; and (ii) signal transduction inhibitors, including proteasome inhibitors, histone deacetylase (HDAC) inhibitors, and B cell receptor (BCR) signaling kinase inhibitors [6]. The availability of targeted therapies has improved treatment options for certain B cell neoplasias in some patients. However, current targeted therapies have important ...

Germinal centers (GCs) are complex multicellular structures in which antigen-specific B cells undergo the molecular remodeling that enables the generation of high-affinity antibodies and the differentiation programs that lead to the generation of plasma–antibody-secreting cells and memory B cells. These reactions are tightly controlled by a variety of mechanisms, including the post-transcriptional control of gene expression by microRNAs (miRNAs). Through the development of animal models with B cell-specific modified miRNA expression, we have contributed to the understanding of the role of miRNAs in the regulation of GC responses and in B cell neoplasia. Here, we review recent advances in the understanding of the role of miRNAs in the regulation of B cell and T follicular helper physiology during the GC response and in the diseases associated to GC response dysregulation.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Brutons tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.