gx-15-070 has been researched along with mocetinostat* in 2 studies
2 other study(ies) available for gx-15-070 and mocetinostat
| Article | Year |
|---|---|
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.
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.. 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.. 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.. 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. Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Histone Deacetylase Inhibitors; HL-60 Cells; Humans; Hydroxamic Acids; Indoles; Leukemia; Microscopy, Electron, Transmission; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Pyrroles; Reverse Transcriptase Polymerase Chain Reaction; Vorinostat | 2010 |
The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.
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. Topics: Apoptosis; Autophagy; Benzamides; BH3 Interacting Domain Death Agonist Protein; Cell Line, Tumor; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Leukemia, Myeloid, Acute; Pyrimidines; Pyrroles; Vorinostat | 2010 |