BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts

S. L. Locatelli, L. Cleris, G. G. Stirparo, S. Tartari, E. Saba, M. Pierdominici, W. Malorni, A. Carbone, A. Anichini, C. Carlo-Stella

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Relapsed/refractory Hodgkin's lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70-80%) and a marked increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P

Original languageEnglish
Pages (from-to)1861-1871
Number of pages11
JournalLeukemia
Volume28
Issue number9
DOIs
Publication statusPublished - 2014

Fingerprint

Hodgkin Disease
Heterografts
Reactive Oxygen Species
Up-Regulation
Cell Line
Cell Death
Histone Deacetylase Inhibitors
Mitogen-Activated Protein Kinase Kinases
Wounds and Injuries
Gene Expression Profiling
Acetylation
Tumor Burden
sorafenib
givinostat
Cell Cycle
Growth

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts. / Locatelli, S. L.; Cleris, L.; Stirparo, G. G.; Tartari, S.; Saba, E.; Pierdominici, M.; Malorni, W.; Carbone, A.; Anichini, A.; Carlo-Stella, C.

In: Leukemia, Vol. 28, No. 9, 2014, p. 1861-1871.

Research output: Contribution to journalArticle

Locatelli, S. L. ; Cleris, L. ; Stirparo, G. G. ; Tartari, S. ; Saba, E. ; Pierdominici, M. ; Malorni, W. ; Carbone, A. ; Anichini, A. ; Carlo-Stella, C. / BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts. In: Leukemia. 2014 ; Vol. 28, No. 9. pp. 1861-1871.
@article{14adb4d8cfd64f33bc2a8c99d62787c6,
title = "BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts",
abstract = "Relapsed/refractory Hodgkin's lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70-80{\%}) and a marked increase in cell death (up to 96{\%}) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50{\%} reduction in tumor burden (P",
author = "Locatelli, {S. L.} and L. Cleris and Stirparo, {G. G.} and S. Tartari and E. Saba and M. Pierdominici and W. Malorni and A. Carbone and A. Anichini and C. Carlo-Stella",
year = "2014",
doi = "10.1038/leu.2014.81",
language = "English",
volume = "28",
pages = "1861--1871",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts

AU - Locatelli, S. L.

AU - Cleris, L.

AU - Stirparo, G. G.

AU - Tartari, S.

AU - Saba, E.

AU - Pierdominici, M.

AU - Malorni, W.

AU - Carbone, A.

AU - Anichini, A.

AU - Carlo-Stella, C.

PY - 2014

Y1 - 2014

N2 - Relapsed/refractory Hodgkin's lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70-80%) and a marked increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P

AB - Relapsed/refractory Hodgkin's lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70-80%) and a marked increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P

UR - http://www.scopus.com/inward/record.url?scp=84908296371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908296371&partnerID=8YFLogxK

U2 - 10.1038/leu.2014.81

DO - 10.1038/leu.2014.81

M3 - Article

C2 - 24561519

AN - SCOPUS:84908296371

VL - 28

SP - 1861

EP - 1871

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 9

ER -