Abstract
Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted.
Highlights
Acute Myeloid Leukemia (AML) if untreated is a rapidly lethal disease, yet limited progress has been achieved in the past three decades for improving the longterm disease-free survival of AML patients using standard chemotherapy regimens [1]
We studied the responses to this treatment regimen (AraC-D2/Carnosic acid (CA)) of AML blasts obtained from patients and placed in primary culture
The results show that the enhancement of apoptosis and total cell death in ex vivo AML blasts was abrogated by the specific caspase 3 inhibitor DEVDCHO [29], but the caspase 1 inhibitor Z-WEHD-fmk [30] had only a minor effect (Table 2A, marked decreases are bolded)
Summary
Acute Myeloid Leukemia (AML) if untreated is a rapidly lethal disease, yet limited progress has been achieved in the past three decades for improving the longterm disease-free survival of AML patients using standard chemotherapy regimens [1]. Modifications of standard chemotherapy are being developed, but none have so far supplanted the decades-old existing regimens. AraC has been combined with other agents, most commonly anthracyclines such as daunorubicin, idarubicin and epirubicin; the anthracenedione mitoxantrone, and the epipodophyllotoxin etoposide (eg, [2, 3]). These and other AraC combinations are extremely toxic, adding to the overall systemic toxicity of the therapy, for instance the cardiotoxicity of the anthracyclines, or of azacytidine combined with AraC [4]
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