Multiple Myeloma | Springer. Link. 4. Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M, Child JA, Comenzo R, Djulbegovic B, Fantl D, Gahrton G, Harousseau JL, Hungria V, Joshua D, Ludwig H, Mehta J, Morales AR, Morgan G, Nouel A, Oken M, Powles R, Roodman D, San Miguel J, Shimizu K, Singhal S, Sirohi B, Sonneveld P, Tricot G, Van Ness B, Scientific Advisors of the International Myeloma Foundation. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J. 2. 00. Pub. Med. Cross. Ref. Bortezomib (VELCADE®) is a proteasome inhibitor that not only targets the myeloma cell, but also acts in the bone marrow micro-environment, inhibiting the binding of. Bcl-2 based cancer medicine, mechanism of action, and clinical trial status. The introduction of novel agents thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, has dramatically improved the outcome of multiple myeloma and. · Induction chemotherapy before autologous stem cell transplantation for symptomatic plasma cell myeloma – does it matter? Bcl- 2. Bcl- 2. Bcl- 2(1. Proteins of the Bcl- 2 family have either. Members of the Bcl- 2 protein include three sub- groups of proteins that promote cell survival (e. Bcl- 2 and Bcl- x. L), initiate cell. Bim, Puma, and Bid), or activate the effector pathways of apoptosis (Bax, Bak).(4) The two isoforms of Bcl- 2, 1. G5. M and 1. G5. O/1. GJH, exhibit. similar fold, but the disparate binding to BAD and BAK proteins, suggesting different anti- apoptotic activity.(1) The intrinsic apoptotic pathway involves. Bcl- 2 family of proteins- mediated alterations in mitochondrial membrane integrity and potential in response to cellular insults or other stress signals.(5). Several Bcl- 2 family members, including Bcl- 2 and Bak, reside not only on mitochondria but also on the ER/nuclear envelope, where they may regulate cytosolic. Ca. 2+ levels.(6) The pro- apoptotic BCL- 2 members are divided into the effector proteins and the BH3- only proteins. It is controversial whether some BH3- domain. Bim or t. Bid) directly activate multidomain pro- apoptotic proteins (e. Bax and Bak) or act via inhibition of those anti- apoptotic Bcl- 2 proteins. Bcl- 2, Bcl- XL, Bcl- w, Mcl- 1, Bfl. A- 1, and Bcl- B) that stabilize pro- apoptotic proteins.(7) The BH3- only proteins sense and relay stress signals, but. Bax or Bak. The BH3- only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro- survival. Bax and Bak from permeabilizing mitochondria.(6) The effector proteins BAK and BAX were originally described to contain. BH1- 3; however, structure- based alignment of globular BCL- 2 family proteins revealed a conserved BH4 motif. The proapoptotic BCL- 2 members are divided. BH3- only proteins. The effector proteins BAK and BAX were originally described to contain only BH1- 3; however. BCL- 2 family proteins revealed a conserved BH4 motif.(8) Upon activation, BAK and BAX homo- oligomerize into proteolipid. OMM to promote MOMP There is a potential third effector molecule, BCL- 2- related ovarian killer (BOK), but no biochemical evidence supports a. BAK or BAX.(9). In most cell types, caspase- 8 catalyzes the cleavage of the pro- apoptotic BH3- only protein Bid into its truncated form, t. Bid. BH- 3 only members of the Bcl- 2 family exclusively engage anti- apoptotic members of the family (Bcl- 2, Bcl- x. L), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro- apoptotic proteins such as Cytc and Smac/DIABLO, an antagonist of IAPs.(1. PUMA is a BH3- only protein that binds and inhibits all of the anti- apoptotic BCL- 2 proteins. It is a direct transcriptional target of p. FOXO3a under conditions of growth factor deprivation. PUMA may also activate BAX and BAK, although it has been shown to promote MOMP predominantly through displacement of other proteins with this function from anti- apoptotic BCL- 2 proteins.(1. The BH3- only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3- only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro- survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria.(6) It is controversial whether some BH3- domain proteins (Bim or t. Bid) directly activate multidomain pro- apoptotic proteins (e. Bax and Bak) or act via inhibition of those anti- apoptotic Bcl- 2 proteins (Bcl- 2, Bcl- XL, Bcl- w, Mcl- 1, Bfl. A- 1, and Bcl- B) that stabilize pro- apoptotic proteins.(7). Cancer cells may escape from apoptosis in response to various stimuli, such as chemotherapy and radiotherapy, by increasing anti- apoptotic proteins of Bcl- 2 protein family, including Bcl- 2, Bcl- x. L, Bcl- w, Mcl- 1 and Bfl- 1.(3) Loss of PUMA accelerates Myc- induced lymphomagenesis. Importantly, in a survey of a large number of human tumors of different types, deletion of PUMA was found to be one of the most common copy- number abnormalities.(1. Clinical studies on ABT- 2. AT- 1. 01 are currently ongoing and whether these compounds can find their way into routine clinical use will depend not only on efficacy but also on manageable, acceptable toxicities. Thrombocytopenia, for example, may limit the value of ABT- 2. Bcl- 2 suppression remain to be determined.(5). Drugs/Indications. News. References. Tumor. Suppress. LEC. Available from: http: //biochemistry. Tumor. Suppress. LEC. Brunelle JK LA. Control of mitochondrial apoptosis by the Bcl- 2 family. J Cell Sci. 2. 00. Pt 4): 4. 37- 4. 1. PMCID: 1. 91. 93. Gul O BH, Kutuk O. Apoptotic blocks and chemotherapy resistance: strategies to identify Bcl- 2 protein signatures. Brief Funct Genomic Proteomic. PMCID: 1. 82. 83. Kelly PN SA. The role of Bcl- 2 and its pro- survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. PMCID: 2. 14. 15. Azmi AS WZ, Philip PA, Mohammad RM, Sarkar FH. Emerging Bcl- 2 inhibitors for the treatment of cancer. Expert Opin Emerg Drugs. PMCID: 2. 08. 12. Adams JM CS. Bcl- 2- regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. PMCID: 1. 76. 29. Kang MH RC. Bcl- 2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2. PMCID: 1. 92. 28. Kvansakul M YH, Fairlie WD, Czabotar PE, Fischer SF, Perugini MA, Huang DC, Colman PM. Vaccinia virus anti- apoptotic F1. L is a novel Bcl- 2- like domain- swapped dimer that binds a highly selective subset of BH3- containing death ligands. Cell Death Differ. PMCID: 1. 85. 51. Chipuk JE MT, Llambi F, Parsons MJ, Green DR. The BCL- 2 family reunion. Mol Cell. 2. 01. 0; 3. PMCID: 2. 01. 59. Schaller MD. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. Journal of Cell Science. Llambi F GD. Apoptosis and oncogenesis: give and take in the BCL- 2 family. Curr Opin Genet Dev. PMCID: 2. 12. 36. Tilly JL. Commuting the death sentence: how oocytes strive to survive. Nature Reviews Molecular Cell Biology. Aim: The aim of this study was to investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human A2. Methods: The viability of human A2. Cell Counting Kit- 8 assay. Cell cycle was detected with flow cytometry analysis. The protein expression levels of Bcl- 2, Bax, β- catenin, cyclin D1, survivin, tissue inhibitor of metalloproteinase (TIMP)- 2, and TIMP- 3 were measured using Western blot analysis. Matrix metalloproteinase (MMP)- 2 and MMP- 9 activity was determined with gelatin zymography. Wound healing assay was used to determine cell migration. Results: Punicalagin inhibited the cell viability of A2. A2. 78. 0 cells was arrested in G1/S phase transition. The treatment also induced apoptosis as shown by the up- regulation of Bax and down- regulation of Bcl- 2. On the other hand, punicalagin treatment increased the expressions of TIMP- 2 and TIMP- 3, decreased the activities of MMP- 2 and MMP- 9, and inhibited cell migration. In addition, the β- catenin pathway was suppressed as shown by the down- regulations of β- catenin and its downstream factors including cyclin D1 and survivin. Conclusions: Punicalagin may have cancer- chemopreventive as well as cancer- chemotherapeutic effects against human ovarian cancer in humans through the inhibition of β- catenin signaling pathway. Restoration of p. Identification of p. PRIMA- 1 holds promise for effective new anticancer therapies. Here, we investigated the effects of small molecule PRIMA- 1 on cell viability and expression of p. NB4 cell line. Our results showed that PRIMA- 1 had antileukemic properties in acute promyelocytic leukemia- derived NB4 cells. PRIMA- 1- triggered apoptosis in a dose- dependent and time- dependent manner as indicated by the MTT assay and annexin- V staining. Apoptosis induction by PRIMA- 1 was associated with caspase- 9, caspase- 7 activation and PARP cleavage. PRIMA- 1 treatment and real- time PCR analysis of proapoptotic p. Bax and Noxa. Western blot analysis showed that I[kappa]B[alpha] phosphorylation and its degradation were inhibited by PRIMA- 1. Moreover, protein expression of nuclear factor- [kappa]B- regulated antiapoptotic (Bcl- 2 and XIAP) and proliferative (c- Myc) gene products was decreased. Importantly, PRIMA- 1 did not show any significant apoptotic effect in normal human peripheral blood mononuclear cells. These in- vitro studies imply that p. Copyright (C) 2. 01. Wolters Kluwer Health, Inc. All rights reserved. CD3. 7 (tetraspanin TSPAN2. B- cell surface antigen widely expressed on mature B- cells.
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