TY - JOUR
T1 - The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy
AU - Wei, Yue
AU - Kadia, Tapan
AU - Tong, Weigang
AU - Zhang, Ming
AU - Jia, Yu
AU - Yang, Hui
AU - Hu, Yumin
AU - Viallet, Jean
AU - O'Brien, Susan
AU - Garcia-Manero, Guillermo
PY - 2010/10/1
Y1 - 2010/10/1
N2 - We analyzed the cellular and molecular effects of two different histone deacetylase inhibitors (HDACi), MGCD0103 and vorinostat, in combination with GX15-070, a BH3-mimetic, in acute myeloid leukemia (AML) cell lines and primary AML cells, and demonstrated that the combination has a synergistic antileukemia effect. We observed that in addition to apoptosis, autophagy also accounts for the observed nonapoptotic decrease of cell viability. Mechanistically, we established a role for calpain activity and ER-located caspase signaling in the induction of both autophagy and apoptosis following this combination of drugs. These findings reveal that for this specific combination, autophagy plays a positive role in inducing cytotoxicity, and that the involved ER signaling networks, as well as their clinical relevance, should be further studied in both preclinical and clinical trials of leukemia and other malignancies.
AB - We analyzed the cellular and molecular effects of two different histone deacetylase inhibitors (HDACi), MGCD0103 and vorinostat, in combination with GX15-070, a BH3-mimetic, in acute myeloid leukemia (AML) cell lines and primary AML cells, and demonstrated that the combination has a synergistic antileukemia effect. We observed that in addition to apoptosis, autophagy also accounts for the observed nonapoptotic decrease of cell viability. Mechanistically, we established a role for calpain activity and ER-located caspase signaling in the induction of both autophagy and apoptosis following this combination of drugs. These findings reveal that for this specific combination, autophagy plays a positive role in inducing cytotoxicity, and that the involved ER signaling networks, as well as their clinical relevance, should be further studied in both preclinical and clinical trials of leukemia and other malignancies.
KW - Apoptosis
KW - Autophagy
KW - GX15-070
KW - Histone deacetylase inhibitor
KW - Leukemia
UR - http://www.scopus.com/inward/record.url?scp=77957688352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957688352&partnerID=8YFLogxK
U2 - 10.4161/auto.6.7.13117
DO - 10.4161/auto.6.7.13117
M3 - Short survey
C2 - 20729640
AN - SCOPUS:77957688352
SN - 1554-8627
VL - 6
SP - 976
EP - 978
JO - Autophagy
JF - Autophagy
IS - 7
ER -