Arabinofuranosyl cytidine (AraC) is an analog of deoxycytidine used as an anticancer drug for leukemic patients. The
effective dose always produces severe complications. The present study investigated the modulation of autophagy and its impact on
the cytotoxicity of AraC toward murine myelogenous leukemia cells (M-NFS-60). Autophagy was inhibited by NH4Cl or Bafilomycin
A1 or enhanced by amino acid starvation, glucose starvation, mild hyperthermia (41 °C), or rapamycin (Rap). Cells were treated with
different concentrations, 0 to 2 μM, of AraC in the presence or absence of autophagy modulators. AraC-induced apoptosis is combined
with autophagy, especially at lower concentrations. This autophagy is characterized by a slow flux, as indicated by levels of LC3B II
and P62 proteins. Inhibition of autophagy did not alter cleaved caspase 3 levels (c-casp.3) or cell viability measured by MTT assays.
Conversely, acceleration of AraC-induced autophagy by co-treatment with autophagy inducers reduced cell viability and increased
c-casp.3 and c-PARP levels. Further, c-PARP levels were reduced in the presence of caspase inhibitor, Z-VAD-FMK. Enhancement of
slow autophagic flux induced by low concentrations of AraC significantly increased the cytotoxicity of AraC toward M-NFS-60 cells.
Such coadministration of autophagy inducers might improve the efficacy of AraC treatment and reduce effective doses.