Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors

Abstract

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38− leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38− subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

“…DSF has anti-cancer activity in vitro and in vivo (Irving and Daniel, 1987;Kast and Belda-Iniesta, 2009;Lin et al, 2011;Morrison et al, 2010;Rezk et al, 2015;Yip et al, 2011). Dimethyl ampal thiolester (DIMATE), an ALDH1 and ALDH3 inhibitor, depletes leukemia stem cells but, importantly, does not affect hematopoietic stem cells (Venton et al, 2016). More recently a potent ALDH1A1 selective inhibitor and a pan-ALDH1A inhibitor were found to synergize with chemotherapy (Huddle et al, 2018;Yang et al, 2018), whereas an ALDH-targeted pro-drug effectively eliminated ALDH bright melanoma cells (Sarvi et al, 2018).…”

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

“…DIMATE is cytotoxic for leukemic stem cells, but not for healthy hematopoietic stem cells. Administration of DIMATE in mice decreases leukemia cells which are derived from acute myeloid leukemia patients and intravenously transplanted [ 122 ]. DIMATE also promotes cell death of melanoma cells and inhibits tumor growth in immunocompetent, immunosuppressed and patient-derived xenograft mouse models [ 123 ].…”

Leukemic stem cells: identification and clinical application

“…In conclusion, ALDH activity can be used as a functional stem cell marker, identifying HSC population and LSC population in AML. Validity to therapeutically target ALDH in AML treatment is controversial; a recent paper showed that in vitro and in vivo inhibition of ALDH selectively eradicates CD34+/CD38−ALDH+ cells [31]. In this study, the authors used the CD34+/CD38−/ALDH+ phenotype to describe LSC, which is distinct from most other studies that define CD34+/CD38−/ALDH+ to reflect HSC.…”