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 language | English |
|---|---|
| Pages (from-to) | 1861-1871 |
| Number of pages | 11 |
| Journal | Leukemia |
| Volume | 28 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2014 |
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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 journal › Article
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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 -