Therapeutic strategies targeting autophagy and hypoxia in human acute myeloid leukemia

Dirkje W. Hanekamp, Roswell Park Cancer Institute

Description

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating in the bone marrow. AML is the most common acute leukemia affecting adults. . Chemotherapeutic approaches have not changed since the 1980s and cure occurs in only 20-30% of treated patients . Recent studies have highlighted the importance of intrinsically low oxygen tension, called hypoxia, within the bone marrow microenvironment. Adaptations by AML cells to hypoxia have been shown to contribute to chemoresistance. We hypothesize that AML cells respond to hypoxia in part by invoking autophagy. Autophagy is a catabolic process leading to the degradation of the cell’s components through the lysosomal machinery, allowing the cell to survive stress from both external as internal environments. Exploiting autophagy in AML treatment could contribute to improved clinical outcomes. We examined the in vitro effects of differing oxygenation, two agents (baflimoycin and chloroquine) known to alter autophagy in other settings, and a hypoxia-activated drug (TH-302), on human AML cell lines. Autophagy was measured by flow cytometry using an autolysosome specific dye. Cell death and apoptosis were measured by MTT assay and flow cytometry. We determined that human AML cells display high basal autophagy levels which are not significantly increased under hypoxia or after TH-302 treatment. Inhibitors of the autophagic pathway are more active under hypoxia and result in synergistic effects on cell death when combined with TH-302. Conclusions: Combination treatment with autophagy inhibitors and a hypoxia-activated drug resulted in improved anti-leukemia effects and may represent a novel therapeutic approach for this disease.

 
Apr 26th, 2:40 PM

Therapeutic strategies targeting autophagy and hypoxia in human acute myeloid leukemia

Edwards 107

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating in the bone marrow. AML is the most common acute leukemia affecting adults. . Chemotherapeutic approaches have not changed since the 1980s and cure occurs in only 20-30% of treated patients . Recent studies have highlighted the importance of intrinsically low oxygen tension, called hypoxia, within the bone marrow microenvironment. Adaptations by AML cells to hypoxia have been shown to contribute to chemoresistance. We hypothesize that AML cells respond to hypoxia in part by invoking autophagy. Autophagy is a catabolic process leading to the degradation of the cell’s components through the lysosomal machinery, allowing the cell to survive stress from both external as internal environments. Exploiting autophagy in AML treatment could contribute to improved clinical outcomes. We examined the in vitro effects of differing oxygenation, two agents (baflimoycin and chloroquine) known to alter autophagy in other settings, and a hypoxia-activated drug (TH-302), on human AML cell lines. Autophagy was measured by flow cytometry using an autolysosome specific dye. Cell death and apoptosis were measured by MTT assay and flow cytometry. We determined that human AML cells display high basal autophagy levels which are not significantly increased under hypoxia or after TH-302 treatment. Inhibitors of the autophagic pathway are more active under hypoxia and result in synergistic effects on cell death when combined with TH-302. Conclusions: Combination treatment with autophagy inhibitors and a hypoxia-activated drug resulted in improved anti-leukemia effects and may represent a novel therapeutic approach for this disease.