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BH3 mimetics

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https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#1
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29580266/synergistic-anti-proliferative-effects-of-combination-of-abt-263-and-mcl-1-selective-inhibitor-a-1210477-on-cervical-cancer-cell-lines
#2
Benedict Shi Xiang Lian, Angeline En Hui Yek, Hemalata Shuvas, Siti Fairus Abdul Rahman, Kalaivani Muniandy, Nethia Mohana-Kumaran
OBJECTIVE: There are number of studies which report that BCL-2 anti-apoptotic proteins (e.g. BCL-2, BCL-XL, and MCL-1) are highly expressed in cervical cancer tissues compared to the normal cervical epithelia. Despite these reports, targeting these proteins for cervical cancer treatment has not been explored extensively. BH3-mimetics that inhibit specific BCL-2 anti-apoptotic proteins may hold encouraging treatment outcomes for cervical cancer management. Hence, the aim of this pilot study is to investigate the sensitivity of cervical cancer cell lines to combination of two BH3-mimetics namely ABT-263 which selectively inhibits BCL-2, BCL-XL and BCL-w and A-1210477, a selective MCL-1 inhibitor...
March 27, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29543705/glycycoumarin-sensitizes-liver-cancer-cells-to-abt-737-by-targeting-de-novo-lipogenesis-and-topk-survivin-axis
#3
Enxiang Zhang, Shutao Yin, Xiaotong Lu, Linhu Ye, Lihong Fan, Hongbo Hu
Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination...
March 15, 2018: Nutrients
https://www.readbyqxmd.com/read/29529398/design-and-screening-of-syringic-acid-analogues-as-bax-activators-an-in-silico-approach-to-discover-bh3-mimetics
#4
Srinivasulu Cheemanapalli, Anuradha C M, Suresh Babu Pakala, Suresh Kumar Chitta
Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach...
March 9, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29520705/targeting-bcl-2-in-hematologic-malignancies
#5
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29507660/flt3-itd-induces-expression-of-pim-kinases-through-stat5-to-confer-resistance-to-the-pi3k-akt-pathway-inhibitors-on-leukemic-cells-by-enhancing-the-mtorc1-mcl-1-pathway
#6
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29459767/mcl-1-and-bcl-x-l-sequestration-of-bak-confers-differential-resistance-to-bh3-only-proteins
#7
Colin Hockings, Amber E Alsop, Stephanie C Fennell, Erinna F Lee, W Douglas Fairlie, Grant Dewson, Ruth M Kluck
The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak...
February 19, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29454280/8-chrysoeriol-as-a-potential-bcl-2-inhibitor-triggers-apoptosis-of-sw1990-pancreatic-cancer-cells
#8
Yiwen Zhang, Zhimei Li, Qiuxia Min, Abulizi Palida, Yiyuan Zhang, Ruotian Tang, Lixia Chen, Hua Li
8-Chrysoeriol, a bioactive flavanoid, was firstly identified to bind directly to BCL-2 as BH3 mimetics by structure-based virtual ligand screening. And 3D docking model revealed the molecular basis of 8-Chrysoeriol targeting to BCL-2. The interaction between 8-Chrysoeriol and BCL-2 was further confirmed using Microscale Thermophoresis (MST) technique. Meanwhile, high expression level of antiapoptotic protein BCL-2 was detected in SW1990 pancreatic cancer cells and 8-Chrysoeriol showed obvious proapoptosis effect against SW1990 in vitro...
February 2, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29441961/clinically-relevant-interactions-of-anti-apoptotic-bcl-2-protein-inhibitors-with-abc-transporters
#9
E Ruzickova, R Janska, P Dolezel, P Mlejnek
In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT-199 below the control level in parental cells...
December 1, 2017: Die Pharmazie
https://www.readbyqxmd.com/read/29434898/abt-737-and-pictilisib-synergistically-enhance-pitavastatin-induced-apoptosis-in-ovarian-cancer-cells
#10
Elizabeth De Wolf, Christopher De Wolf, Alan Richardson
There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29408011/bh3-mimetics-as-antifibrotic-therapy-unleashing-the-mitochondrial-pathway-of-apoptosis-in-myofibroblasts
#11
REVIEW
Tobias Kuehl, David Lagares
Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases...
January 30, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29394130/dznep-represses-bcl-2-expression-and-modulates-apoptosis-sensitivity-in-response-to-nutlin-3a
#12
Yalu Zhou, Ricardo E Perez, Lei Duan, Carl G Maki
MDM2 antagonists stabilize and activate wild-type p53, and histone methyltransferase (HMT) inhibitors reduce methylation on histone lysines and arginines. Both MDM2 antagonists and HMT inhibitors are being developed as cancer therapeutics. Wild-type p53 expressing HCT116 colon cancer cells were resistant to apoptosis in response to the MDM2 antagonist Nutlin-3a. However, co-treatment with the HMT inhibitor DZNep sensitized the cells to Nutlin-3a-induced apoptosis. This sensitization resulted from reduced activity of the Bcl-2 gene promoter and a reduction in Bcl-2 mRNA and protein...
February 2, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29381777/the-akt-bcl-2-axis-mediates-survival-of-uterine-leiomyoma-in-a-novel-3d-spheroid-model
#13
Vania Vidimar, Debabrata Chakravarti, Serdar E Bulun, Ping Yin, Romana Nowak, Jian-Jun Wei, J Julie Kim
A deeper understanding of the pathways that drive uterine leiomyoma (ULM) growth and survival requires model systems that more closely mimic the in vivo tumors. This would provide new insights into developing effective therapeutic strategies for these common benign tumors of childbearing-aged women. In this study, we examined the role of BCL-2 in mediating ULM survival in the context of increased AKT and oxidative stress using a novel 3-dimensional (3D), spheroid-based model that more closely resembles the native ULM tumor microenvironment...
January 26, 2018: Endocrinology
https://www.readbyqxmd.com/read/29374168/downregulation-of-mcl-1-and-upregulation-of-puma-using-mtor-inhibitors-enhance-antitumor-efficacy-of-bh3-mimetics-in-triple-negative-breast-cancer
#14
Haolong Li, Lei Liu, Haocai Chang, Zhengzhi Zou, Da Xing
Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other breast cancer subtypes. Albeit that chemotherapy is the first choice for TNBC treatment, rapid emergence of chemoresistance and variability of chemotherapeutic responses in TNBC patients call for novel therapeutic strategies. Here, we reported evidences highlighting that combination of BH3 mimetics and mTOR inhibitors could be a promising therapeutic strategy to improve TNBC treatment. Our results showed that combination of the BH3 mimetic ABT263 and typical mTOR inhibitors, BEZ235 or AZD8055, leads to efficient apoptosis in vitro...
January 26, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29372687/cyclin-dependent-kinase-2-inhibitor-su9516-increases-sensitivity-of-colorectal-carcinoma-cells-caco-2-but-not-ht29-to-bh3-mimetic-abt-737
#15
Andrea Štefaniková, Katarína Klačanová, Ivana Pilchová, Jozef Hatok, Peter Račay
Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737...
December 2017: General Physiology and Biophysics
https://www.readbyqxmd.com/read/29371599/cell-death-based-treatment-of-childhood-cancer
#16
REVIEW
Mike-Andrew Westhoff, Nicolas Marschall, Michael Grunert, Georg Karpel-Massler, Stefan Burdach, Klaus-Michael Debatin
Any therapy that aims at eradicating a cancerous growth will have at its core a cell death-inducing component. Here we argue that paediatric oncology presents with its unique set of considerations and problems, which-while taking the lead from oncological research experiences obtained from the adult population-need to be clinically evaluated independently. This is particularly true when considering long-term side effects. Precision medicine offers a promising new approach in therapy, but given as a monotherapy and in a limited combination, as found in an apoptosis inducer/sensitiser combination, it will most likely lead to mutation escape of the target cell population and the emergence of resistance...
January 25, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348439/dual-suppression-of-inner-and-outer-mitochondrial-membrane-functions-augments-apoptotic-responses-to-oncogenic-mapk-inhibition
#17
Madhavika N Serasinghe, Jesse D Gelles, Kent Li, Lauren Zhao, Franco Abbate, Marie Syku, Jarvier N Mohammed, Brateil Badal, Cuahutlehuanitzin A Rangel, Kyle L Hoehn, Julide Tok Celebi, Jerry Edward Chipuk
Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAFV600E melanoma cells eliminate glycolysis upon inhibition of BRAFV600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29340082/reciprocal-sensitivity-of-diffuse-large-b-cell-lymphoma-cells-to-bcl-2-inhibitors-bird-2-versus-venetoclax
#18
Tamara Vervloessem, Haidar Akl, Thomas Tousseyn, Humbert De Smedt, Jan B Parys, Geert Bultynck
Bcl-2 is often upregulated in cancers to neutralize the BH3-only protein Bim at the mitochondria. BH3 mimetics (e.g. ABT-199 (venetoclax)) kill cancer cells by targeting Bcl-2's hydrophobic cleft and disrupting Bcl-2/Bim complexes. Some cancers with elevated Bcl-2 display poor responses towards BH3 mimetics, suggesting an additional function for anti-apoptotic Bcl-2 in these cancers. Indeed, Bcl-2 via its BH4 domain prevents cytotoxic Ca2+ release from the endoplasmic reticulum (ER) by directly inhibiting the inositol 1,4,5-trisphosphate receptor (IP3 R)...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29335437/deubiquitinase-usp13-dictates-mcl1-stability-and-sensitivity-to-bh3-mimetic-inhibitors
#19
Shengzhe Zhang, Meiying Zhang, Ying Jing, Xia Yin, Pengfei Ma, Zhenfeng Zhang, Xiaojie Wang, Wen Di, Guanglei Zhuang
MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29312548/mimicking-the-bim-bh3-domain-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutant-non-small-cell-lung-cancer
#20
Jinjing Xia, Hao Bai, Bo Yan, Rong Li, Minhua Shao, Liwen Xiong, Baohui Han
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12...
December 12, 2017: Oncotarget
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