Literature DB >> 25282334

Multiple mechanisms contribute to the synergistic anti-myeloma activity of the pan-histone deacetylase inhibitor LBH589 and the rapalog RAD001.

Vijay Ramakrishnan1, Teresa Kimlinger1, Michael Timm1, Jessica Haug1, S Vincent Rajkumar1, Shaji Kumar2.   

Abstract

We examined the pre-clinical activity of pan-histone deacetylase inhibitor LBH589 in combination with mTORC1 inhibitor RAD001 and observed that the drug combination strongly synergized in inducing cytotoxicity in multiple myeloma (MM) cells. LBH589 caused an increase in acetylated histones and RAD001 inhibited mTORC1 activity. RAD001 caused potent G0/G1 arrest while LBH589 induced pronounced apoptosis, both of which were enhanced when the drugs were used in combination. LBH589/RAD001 combination led to down regulation of pStat3, cyclins, CDKs and XIAP and up regulation of pro-apoptotic Bcl-2 family proteins. A clinical trial is underway using LBH589/RAD001 combination in relapsed MM patients.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Apoptosis; Histone deacetylase inhibitor; Multiple myeloma; Proliferation; mTOR inhibitor

Mesh：

Substances：

Year:  2014        PMID： 25282334      PMCID： PMC5645028          DOI： 10.1016/j.leukres.2014.09.004

Source DB:  PubMed          Journal:  Leuk Res        ISSN： 0145-2126            Impact factor:   3.156


  49 in total

Review 1.  Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics.

Authors:  Anton Eberharter; Peter B Becker
Journal:  EMBO Rep       Date:  2002-03       Impact factor: 8.807

2.  Clinical and biological significance of RAS mutations in multiple myeloma.

Authors:  W J Chng; N Gonzalez-Paz; T Price-Troska; S Jacobus; S V Rajkumar; M M Oken; R A Kyle; K J Henderson; S Van Wier; P Greipp; B Van Ness; R Fonseca
Journal:  Leukemia       Date:  2008-06-05       Impact factor: 11.528

3.  Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells.

Authors:  Teru Hideshima; Laurence Catley; Hiroshi Yasui; Kenji Ishitsuka; Noopur Raje; Constantine Mitsiades; Klaus Podar; Nikhil C Munshi; Dharminder Chauhan; Paul G Richardson; Kenneth C Anderson
Journal:  Blood       Date:  2006-01-17       Impact factor: 22.113

4.  MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma.

Authors:  V Ramakrishnan; S Ansell; J Haug; D Grote; T Kimlinger; M Stenson; M Timm; L Wellik; T Halling; S V Rajkumar; S Kumar
Journal:  Leukemia       Date:  2011-08-09       Impact factor: 11.528

5.  Histone deacetylase inhibitors in the treatment for multiple myeloma.

Authors:  Teru Hideshima; Kenneth C Anderson
Journal:  Int J Hematol       Date:  2013-03-10       Impact factor: 2.490

Review 6.  Targeting Histone Deacetylases in Diseases: Where Are We?

Authors:  Rosaria Benedetti; Mariarosaria Conte; Lucia Altucci
Journal:  Antioxid Redox Signal       Date:  2014-03-06       Impact factor: 8.401

7.  Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma.

Authors:  Ruben Niesvizky; Scott Ely; Tomer Mark; Sangeeta Aggarwal; Janice L Gabrilove; John J Wright; Selina Chen-Kiang; Joseph A Sparano
Journal:  Cancer       Date:  2010-09-22       Impact factor: 6.860

8.  The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.

Authors:  Patricia Maiso; Xonia Carvajal-Vergara; Enrique M Ocio; Ricardo López-Pérez; Gema Mateo; Norma Gutiérrez; Peter Atadja; Atanasio Pandiella; Jesús F San Miguel
Journal:  Cancer Res       Date:  2006-06-01       Impact factor: 12.701

9.  Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma.

Authors:  Angela Zöllinger; Thorsten Stühmer; Manik Chatterjee; Stefan Gattenlöhner; Eugenia Haralambieva; Hans-Konrad Müller-Hermelink; Mindaugas Andrulis; Axel Greiner; Carmen Wesemeier; Jörg C Rath; Hermann Einsele; Ralf C Bargou
Journal:  Blood       Date:  2008-07-17       Impact factor: 22.113

10.  SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.

Authors:  Thomas Porstmann; Claudio R Santos; Beatrice Griffiths; Megan Cully; Mary Wu; Sally Leevers; John R Griffiths; Yuen-Li Chung; Almut Schulze
Journal:  Cell Metab       Date:  2008-09       Impact factor: 27.287
View more
  2 in total

1.  Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma.

Authors:  Vijay G Ramakrishnan; Kevin C Miller; Elaine P Macon; Teresa K Kimlinger; Jessica Haug; Sanjay Kumar; Wilson I Gonsalves; S Vincent Rajkumar; Shaji K Kumar
Journal:  Haematologica       Date:  2019-03-07       Impact factor: 9.941

Review 2.  Clinical use and applications of histone deacetylase inhibitors in multiple myeloma.

Authors:  Nidhi Tandon; Vijay Ramakrishnan; Shaji K Kumar
Journal:  Clin Pharmacol       Date:  2016-05-06
  2 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.