Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the
presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first-line treatment
for CML, and some treatment resistance has been reported. Natural products are rich
sources of bioactive compounds with biological effects, opening a possibility to alter
cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference
of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible
synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid
presented an IC50 of 14.0 µM and 19.6 µM for K562 and Lucena 1, respectively, whilst betulinic acid
presented an IC50 of 8.6 µM and 12.5 µM for these cell lines. Evaluation of the combination of terpenoids
and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism
with IMA, as indicated by the combination indexes (CI<1). Analysis of
annexin V labeling demonstrated that a combination of IMA with betulinic acid enhances
the inhibition on cell proliferation via the apoptosis pathway, with caspases 3/7
activation after 24 hours of treatment and inhibition of the STAT5/survivin pathway,
decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant
leukemia cell line is a promising strategy for CML treatment.
Keywords
cancer - betulinic acid - ursolic acid - synergism - MDR
