GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy

• Published in: Cell death & disease Vol. 1; no. 9; p. e76
• Main Authors: Heidari, N, Hicks, M A, Harada, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2010; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/80/82; 692/699/67/1990/283/2125; 692/700/565/1436; Antibodies; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy-Related Protein 5; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Beclin-1; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Glucocorticoids - therapeutic use; Humans; Immunology; Life Sciences; Membrane Proteins - metabolism; Microtubule-Associated Proteins - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Original; original-article; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrroles - therapeutic use; RNA Interference; RNA, Small Interfering - metabolism; obatoclax; apoptosis; glucocorticoid; autophagy; acute lymphoblastic leukemia; MCL-1
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2010.53

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy.