Read by QxMD icon Read

BH3 mimetics

Jeremy L Yap, Lijia Chen, Maryanna E Lanning, Steven Fletcher
A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the anti-apoptotic members of the Bcl-2 family of proteins. The prosurvival function of the anti-apoptotic Bcl-2 proteins is manifested by capturing the pro-apoptotic Bcl-2 proteins through their BH3 death domains. Accordingly, strategies to antagonize the anti-apoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic and selective BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and pro-apoptotic Bcl-2 proteins...
October 17, 2016: Journal of Medicinal Chemistry
Gilad Itchaki, Jennifer R Brown
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN...
October 2016: Therapeutic Advances in Hematology
Leona Rohrbeck, Jia-Nan Gong, Erinna F Lee, Andrew J Kueh, Andreas Behren, Lin Tai, Guillaume Lessene, David C S Huang, Walter D Fairlie, Andreas Strasser, Marco J Herold
A large proportion of melanomas harbour the activating BRAF(V600E) mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF(V600E) kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM...
September 30, 2016: Cell Death and Differentiation
Victor Peperzak, Erik Slinger, Johanna Ter Burg, Eric Eldering
For successful treatment of malignant B-cells it is crucial to understand intrinsic survival requirements in relation to their normal progenitors. Long-lived humoral immunity as well as most B-cell malignancies, originate in the germinal center (GC). Murine GC B-cells depend on pro-survival protein MCL-1, but not BCL-XL. In contrast, naive and memory B-cells depend on BCL-2, but not BCL-XL or MCL-1. For human B-cell subsets, the functional relationships among BCL-2 members are unclear, and also if and how they shift after malignant transformation...
September 30, 2016: Cell Death and Differentiation
Camila Rubio-Patiño, Jozef P Bossowski, Elodie Villa, Laura Mondragón, Barbara Zunino, Emma Proïcs, Johanna Chiche, Frédéric Bost, Els Verhoeyen, Jean-Ehrland Ricci
Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food...
September 28, 2016: Oncotarget
L Yang
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Heidi Gytz, Mariann F Hansen, Signe Skovbjerg, Anders C M Kristensen, Sofie Hørlyck, Mette B Jensen, Marlene Fredborg, Lotte D Markert, Nigel A McMillan, Erik I Christensen, Pia M Martensen
BACKGROUND INFORMATION: Interferons are a family of cytokines with growth inhibitory and antiviral functions, which exert their biological actions through the expression of Interferon Stimulated Genes, ISGs. The human ISG12 family of proteins comprises ISG12A, ISG12B, ISG12C and ISG6-16. Due to differential splicing and a gene variation, the human ISG12A protein exists as a full-length ISG12A form and three ISG12A variants. ISG12 has been found transcriptionally dysregulated in many disorders...
September 27, 2016: Biology of the Cell
Monica Benvenuto, Rosanna Mattera, Laura Masuelli, Gloria Taffera, Orlando Andracchio, Ilaria Tresoldi, Paolo Lido, Maria Gabriella Giganti, Justyna Godos, Andrea Modesti, Roberto Bei
Racemic Gossypol [(±)-GOS], composed of both (-)-GOS and (+)-GOS, is a small BH3-mimetic polyphenol derived from cotton seeds. (±)-GOS has been employed and well tolerated by cancer patients. Head and neck carcinoma (HNC) represents one of the most fatal cancers worldwide, and a significant proportion of HNC expresses high levels of antiapoptotic Bcl-2 proteins. In this study, we demonstrate that (±)-GOS inhibits cell proliferation and induces apoptosis and autophagy of human pharynx, tongue, and salivary gland cancer cell lines and of mouse salivary gland cancer cells (SALTO)...
September 27, 2016: International Journal of Food Sciences and Nutrition
Juraj Bodo, Xiaoxian Zhao, Lisa Durkin, Andrew J Souers, Darren C Phillips, Mitchell R Smith, Eric D Hsi
The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential...
September 20, 2016: Oncotarget
Lee-Han Kim, Ji-Ae Shin, Boonsil Jang, In-Hyoung Yang, Dong-Hoon Won, Joseph H Jeong, Tae-Ho Chung, Nam-Pyo Cho, Sung-Dae Cho
OBJECTIVE: The mimetic BH3 ABT-737, a potent inhibitor of anti-apoptotic Bcl-2 family proteins, has potential as anti-cancer drug in many cancers. Recently, patients treated with ABT-737 have developed drug tolerance during cancer therapy. Therefore, we examined whether ABT-737 is effective in killing MC-3 and HSC-3 human oral cancer cells either alone or in combination with the oncogenic kinase inhibitor, sorafenib. DESIGN: The potentiating activities of sorafenib in ABT-737-induced apoptosis were determined using trypan blue exclusion assay, DAPI staining, cell viability assay and Western blot analysis...
August 31, 2016: Archives of Oral Biology
Yvonne de Jong, Annemiek M van Maldegem, Adrian Marino-Enriquez, Danielle de Jong, Johnny Suijker, Inge H Briaire-de Bruijn, Alwine B Kruisselbrink, Anne-Marie Cleton-Jansen, Karoly Szuhai, Hans Gelderblom, Jonathan A Fletcher, Judith V M G Bovée
Mesenchymal chondrosarcomas are rare and highly aggressive sarcomas occurring in bone and soft tissue, with poor overall survival. Bcl-2 expression was previously shown to be upregulated in mesenchymal chondrosarcomas. We here report on a newly derived mesenchymal chondrosarcoma cell line, MCS170, in which we investigated treatment with the BH3 mimetic ABT-737 alone or in combination with conventional chemotherapy as a possible new therapeutic strategy. The presence of the characteristic HEY1-NCOA2 fusion was confirmed in the MCS170 cell line using FISH, RT-PCR, and sequencing...
October 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Wenying Ren, Raghav Joshi, Paul Mathew
: The bone-conserved metastatic phenotype of prostate cancer is a prototype of non-random metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells...
September 2, 2016: Molecular Cancer Research: MCR
Rebecca A Bilardi, Natasha S Anstee, Stefan P Glaser, Mikara Robati, Cassandra J Vandenberg, Suzanne Cory
Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model...
2016: Cell Death & Disease
Mary Speir, Kate E Lawlor, Stefan P Glaser, Gilu Abraham, Seong Chow, Adam Vogrin, Keith E Schulze, Ralf Schuelein, Lorraine A O'Reilly, Kylie Mason, Elizabeth L Hartland, Trevor Lithgow, Andreas Strasser, Guillaume Lessene, David C S Huang, James E Vince, Thomas Naderer
Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1...
2016: Nature Microbiology
Tao Hu, Zhen Li, Chun-Ying Gao, Chi Hin Cho
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects...
August 14, 2016: World Journal of Gastroenterology: WJG
Ingela B Vikström, Anne Slomp, Emma M Carrington, Laura M Moesbergen, Catherine Chang, Gemma L Kelly, Stefan P Glaser, J H Marco Jansen, Jeanette H W Leusen, Andreas Strasser, David C S Huang, Andrew M Lew, Victor Peperzak, David M Tarlinton
Pro-survival BCL-2 family members protect cells from programmed cell death that can be induced by multiple internal or external cues. Within the haematopoietic lineages, the BCL-2 family members BCL-2, BCL-XL and MCL-1 are known to support cell survival but the individual and overlapping roles of these pro-survival BCL-2 proteins for the persistence of individual leukocyte subsets in vivo has not yet been determined. By combining inducible knockout mouse models with the BH3-mimetic compound ABT-737, which inhibits BCL-2, BCL-XL and BCL-W, we found that dependency on MCL-1, BCL-XL or BCL-2 expression changes during B-cell development...
2016: Cell Death & Disease
Ryan S Soderquist, Alan Eastman
Antiapoptotic BCL2 proteins play a major role in tumor cell survival. Hence, BCL2 inhibitors have been developed as direct inducers of apoptosis. ABT-199 (venetoclax) received breakthrough therapy designation from the FDA due to its apparent efficacy in CLL and AML. However, resistance to ABT-199 is mediated by other BCL2 proteins including BCLXL and MCL1. Considerable effort has been expended seeking novel "BH3 mimetics" that inhibit all of these BCL2 proteins. While many BH3 mimetics inhibit BCL2 proteins in vitro, they fail to directly inhibit them in intact cells...
September 2016: Molecular Cancer Therapeutics
Ailsa Bennett, Olivia Sloss, Caroline Topham, Louisa Nelson, Anthony Tighe, Stephen S Taylor
Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic-mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC-mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly...
August 2016: Open Biology
Prasad Sulkshane, Tanuja Teni
We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200-400 nM concentration which correlated with their MCL-1 expression...
August 5, 2016: Oncotarget
S I Wang, Ying Mao, Song Xi, Xinxue Wang, Liankun Sun
The aberrant proliferation of tumor cells necessitates compensatory changes in tumor metabolic processes. Previous studies on tumor growth and metabolism have established a relationship between nutrient stress and Bcl-2 anti-apoptotic proteins, although the mechanisms connecting these processes remain unclear. We induced nutrient deprivation in human ovarian cancer SKOV3 cells by culturing cells in Earle's Balanced Salt Solution (EBSS) as a starvation model. We used EBSS treatment with the BH3 domain of Bcl-2 family proteins (BH3) mimetic ABT737, which targets Bcl-2/Bcl-xL, to examine mitochondrial dynamics and the interactive regulatory mechanisms between nutrition and Bcl-2 proteins...
August 2, 2016: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"