1,721,123 research outputs found
The role of NF-kappaB in lymphoid malignancies
No full textNuclear Factor kappaB (NF-kappaB) transcription factors are central regulators of lymphocyte proliferation, survival and development. Although normally subject to tight control, constitutive activation of NF-kappaB promotes inappropriate lymphocyte survival and proliferation, and is recognised as key pathological feature in various lymphoid malignancies. Inhibition of NF-kappaB may be an attractive therapeutic approach in these diseases. This review focuses on the mechanisms and functional consequences of NF-kappaB activation in lymphoid malignancies and potential therapeutic strategies for inhibition of NF-kappaB.<br/
Purification of primary malignant B-cells and immunoblot analysis of bcl-2 family proteins
No full textThe ability to isolate relatively pure populations of primary normal and malignant lymphocytes has brought studies of lymphoid malignancies to the forefront of cancer research. Apoptosis (programmed cell death) plays a key role in controlling normal B-cell numbers, and resistance to apoptosis contributes to lymphomagenesis and reduces the effectiveness of chemotherapy and radiotherapy. Multiple Bcl-2 family proteins orchestrate key life and death decisions in lymphocytes, and the prototypical family member, Bcl-2, is activated by reciprocal translocation in human lymphoma. Here, we describe an immunomagnetic method to isolate and purify malignant B-cells suitable for in vitro analyses from lymph node biopsies. Methods to analyze the expression of Bcl-2 family proteins by immunoblotting also are described
Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia
No full textChronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world and exists as subtypes with very different clinical courses. CLL is generally described as a disease of failed apoptosis. Apoptosis resistance may stem from a combination of microenvironmental survival signals as well as from intrinsic alterations in the apoptotic machinery within the CLL cell. The molecular mechanism involved in controlling apoptosis in CLL is complex and is influenced by many factors, including Bcl-2 family proteins, which are critical regulators of cell death. Here we review the significance of apoptosis dysregulation in CLL, focusing on the role of Bcl-2 and related Bcl-2 family proteins, such as Bax and Mcl-1. The differential properties of the newly described subsets of CLL are also highlighted
BAG-1 prevents stress-induced apoptosis and long term growth inhibition in breast cancer cells via an HSC70/HSP70-dependent pathway
No full textInvestigational epigenetically targeted drugs in early phase trials for the treatment of haematological malignancies
No full textThe identification of recurring alterations in components of the epigenome of leukaemia and lymphoma has driven the rapid development of highly potent epigenetically targeted therapies. This rapid development has alluded to the possibility of a personalised therapeutic approach in selected patient populations. An enhanced understanding of the biological effects of these epigenetic alterations in initiation and progression of haematological malignancies, together with a clear mechanistic insight into how the drugs reverse the phenotypes, will define their translation into routine clinical use
Targeted inhibition of mRNA translation initiation factors as a novel therapeutic strategy for mature B-cell neoplasms
No full textCancer development is frequently associated with dysregulation of mRNA translation to enhance both increased global protein synthesis and translation of specific mRNAs encoding oncoproteins. Thus, targeted inhibition of mRNA translation is viewed as a promising new approach for cancer therapy. In this article we review current progress in investigating dysregulation of mRNA translation initiation in mature B-cell neoplasms, focusing on chronic lymphocytic leukemia, follicular lymphoma and diffuse large B-cell lymphoma. We discuss mechanisms and regulation of mRNA translation, potential pathways by which genetic alterations and the tumor microenvironment alters mRNA translation in malignant B cells, preclinical evaluation of drugs targeted against specific eukaryotic initiation factors and current progress towards clinical development. Overall, inhibition of mRNA translation initiation factors is an exciting and promising area for development of novel targeted anti-tumor drugs
Regulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Burkitt's lymphoma cell lines
No full textTumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in sensitive cells and may be suitable for novel anti-cancer therapies aimed at inducing apoptosis via the activation of TRAIL receptors on malignant cells. Here we have characterized the TRAIL sensitivity of a panel of Burkitt's lymphoma (BL) cell lines. Overall, 5/12 BL cell lines and 1/2 lymphoblastoid cell lines were sensitive to TRAIL-induced apoptosis, although only one BL cell line approached the sensitivity of Jurkat cells, a widely used model for TRAIL-induced apoptosis. Whereas, 4/5 of the Epstein–Barr virus (EBV)-negative cell lines were TRAIL sensitive, only 1/7 EBV-positive BL cell lines were TRAIL sensitive. However, isogenic BL cell lines with different EBV status were not differently sensitive to TRAIL, indicating that EBV is not a major determinant of TRAIL sensitivity. All cell lines expressed the death receptor (DR)5 TRAIL receptor, whereas expression of DR4 was more variable. Differences in the expression of downstream signalling molecules [Fas-associated death domain protein (FADD), caspase 8] and inhibitors [decoy receptor 1 (DcR1), cellular FLICE-like inhibitory protein (c-FLIP)] did not correlate with TRAIL sensitivity. Therefore, a subset of BL cell lines are sensitive to TRAIL-induced apoptosis, however, the molecular mechanism that determines responsiveness remains to be identified
Macrolactamization versus macrolactonization: total synthesis of FK228, the depsipeptide histone deacetylase inhibitor
No full textThe cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.<br/
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