The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.
OBJECTIVE
Single-agent histone deacetylase inhibitors (HDACi) have limited clinical activity in human leukemia. Although the way HDACi exert their antileukemia effect is not fully understood, it is accepted that induction of apoptosis is important. We hypothesized, therefore, that combination of an HDACi with a proapoptotic agent, such as the Bcl-2 homology domain-3 mimetic GX15-070, could result in enhanced antileukemia activity.


METHODS
We analyzed the cellular and molecular effects of two different HDACi (MGCD0103 and vorinostat) in combination with GX15-070 in leukemia cell lines and primary acute myelogenous leukemia cells.


RESULTS
We showed that the combination had synergistic antileukemia effect both in leukemia cell lines and in primary acute myelogenous leukemia cells. Using molecular markers and electron microscopy, we observed that in addition to apoptosis, autophagy accounts for the nonapoptotic decrease in cell viability, an effect that could be inhibited by chloroquine, an inhibitor of autophagy. Finally, we established a role for calpain activity in the induction of both autophagy and apoptosis by this combination.


CONCLUSIONS
The combination of an HDACi and GX15-070 has synergistic antileukemia activity, and the effect is mediated by induction of apoptosis and autophagy. The combination should be studied in clinical trials of leukemia and the role of autophagy in leukemia therapy needs to be better understood.
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Yue
Y
Wei
Tapan
T
Kadia
Weigang
W
Tong
Ming
M
Zhang
Yu
Y
Jia
Hui
H
Yang
Yumin
Y
Hu
Francesco Paolo
FP
Tambaro
Jean
J
Viallet
Susan
S
O'Brien
Guillermo
G
Garcia-Manero
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077337:Vorinostat
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; D000077337:Vorinostat; C523184:mocetinostat; C520962:obatoclax