Therapeutic strategies targeting autophagy and hypoxia in human acute myeloid leukemia
Hanekamp, Dirkje W.
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Acute myeloid leukemia (AML) is a disease of abnormal immature myeloblasts. While the biological characterization of AML has witnessed substantial progress, chemotherapeutic approaches targeting AML have not been changed since the 1980s, and long-term cure is still realized in only 20-30% of the patients. Recent studies have highlighted the importance of intrinsically low oxygen tension, called hypoxia within the bone marrow microenvironment. Hypoxia-inducible factors are transcription factors which rapidly respond to hypoxic environments by inducing a cell survival response engaging autophagy. This leads to the degradation of the cell's components through the lysosomal machinery, allowing the cell to survive stress from both external as well as internal environments. In hematological malignancies, autophagy is suspected to act as either a chemo resistance mechanism, or as a tumor suppressor. In addition, autophagy is suspected to be involved in promoting immune competence and anti-cancer immunity, eventually leading to enhanced tolerance to standard treatments. Previous preclinical findings using TH-302, a hypoxia-activated nitrogen mustard derivative prodrug, concluded that TH-302 demonstrated anti-tumor activity in human AML cell lines, as well as in vivo models. Treatment with TH-302 inhibited leukemic burden and prolonged survival in two systemic human AML xenograft models at doses comparable to that used in clinical trials. Since autophagy is a `downstream' effect, frequently induced by hypoxia, agents targeting autophagy could have the same effect. Moreover, autophagy is often mentioned as survival mechanisms allowing cells to overcome its initial insult caused by other chemotherapeutic agents. We hypothesize that combining these drugs to treatments with TH-302 could increase its effect. In this study we investigated whether exploiting autophagy in AML treatment could contribute to improved clinical outcomes. We examined the effect of autophagy inhibitors and inducers as single agents, as well as in combination with novel hypoxia-targeted drugs on multiple leukemia cell lines under both normoxic and hypoxic conditions. The efficacy of the drugs were determined by observing their ability to induce apoptosis, DNA damage and its effects on cell cycle status. Systemic human AML mouse models were used to determine effects on in vivo disease progression and survival. The results presented here show that targeting autophagy and hypoxia in the marrow microenvironment holds promise for the future treatments of blood cancers. However, targeting both hypoxia and autophagy simultaneously did not show improvement over single agent treatment with agents targeting either hypoxia or autophagy. Based on these results, we hypothesize that targeting autophagy or hypoxia could be more beneficial when combined with other therapeutic agents, outside of these postulated hypoxia-autophagy pathways. We demonstrate some initial results supporting this hypothesis, but additional studies are needed to verify these findings.