Treatment of acute myeloid leukemia (AML) largely depends on chemotherapy, but current regimens have been unsatisfactory for long-term remission. Although differentiation induction therapy utilizing 1,25(OH) D (VD3) has shown great promise for the improvement of AML treatment efficacy, severe side effects caused by its supraphysiological dose limit its clinical application. Here we investigated the combinatorial effect of l-asparaginase (ASNase)-mediated amino acid depletion and the latent alternation of VD3 activity on the induction of myeloid differentiation. ASNase treatment enhanced VD3-driven phenotypic and functional differentiation of three-different AML cell lines into monocyte/macrophages, along with c-Myc downregulation. Using gene silencing with shRNA and a chemical blocker, we found that reduced c-Myc is a critical factor for improving VD3 efficacy. c-Myc-dependent inhibition of mTORC1 signaling and induction of autophagy were involved in the enhanced AML cell differentiation. In addition, in a postculture of AML cells after each treatment, ASNase supports the antileukemic effect of VD3 by inhibiting cell growth and inducing apoptosis. Finally, we confirmed that the administration of ASNase significantly improved VD3 efficacy in the prolongation of survival time in mice bearing tumor xenograft. Our results are the first to demonstrate the extended application of ASNase, which is currently used for acute lymphoid leukemia, in VD3-mediated differentiation induction therapy for AML, and suggest that this drug combination may be a promising novel strategy for curing AML.

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Oxidatively treated carbon nanotubes were coated on a glassy carbon surface to form a CNT-layer. On the CNTlayered GC surface, a redox hydrogel film of the copolymer, of polyacryamide and poly(N-vinylimidazole) complexed with [Os(4,4'-dichloro-2,2'-bipyridine) 2 Cl] + /2 + wiring bilirubin oxidase was immobilized. A good contact was achieved between the hydrogel film and the hydrophilic CNT-layer with carboxylated CNTs. The prepared bilirubin oxidase cathode on the CNT-layer was employed for the electrocatalytic reduction of O 2 , and enhanced current and stability were observed. Electron transfers from the electrode surface O 2 molecules were analyzed. The optimal composition of the enzyme, redox polymer, and cross-linker in the catalyst and the thickness of the CNT-layer were determined.

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