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

Vijay Ramakrishnan; Teresa Kimlinger; Michael Timm; Jessica Haug; S. Vincent Rajkumar; Shaji Kumar

doi:10.1016/j.leukres.2014.09.004

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

Vijay Ramakrishnan, Teresa Kimlinger, Michael Timm, Jessica Haug, S. Vincent Rajkumar, Shaji Kumar

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1358-1366
Number of pages	9
Journal	Leukemia Research
Volume	38
Issue number	11
DOIs	https://doi.org/10.1016/j.leukres.2014.09.004
State	Published - Nov 1 2014

Keywords

Apoptosis
Histone deacetylase inhibitor
MTOR inhibitor
Multiple myeloma
Proliferation

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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10.1016/j.leukres.2014.09.004

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title = "Multiple mechanisms contribute to the synergistic anti-myeloma activity of the pan-histone deacetylase inhibitor LBH589 and the rapalog RAD001",

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.",

keywords = "Apoptosis, Histone deacetylase inhibitor, MTOR inhibitor, Multiple myeloma, Proliferation",

author = "Vijay Ramakrishnan and Teresa Kimlinger and Michael Timm and Jessica Haug and Rajkumar, {S. Vincent} and Shaji Kumar",

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AU - Ramakrishnan, Vijay

AU - Kimlinger, Teresa

AU - Timm, Michael

AU - Haug, Jessica

AU - Rajkumar, S. Vincent

AU - Kumar, Shaji

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Histone deacetylase inhibitor

KW - MTOR inhibitor

KW - Multiple myeloma

KW - Proliferation

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

Abstract

Keywords

ASJC Scopus subject areas

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