Differentiation-Inducing Effects of Triciribine and All-Trans Retinoic Acid in Acute Myeloid Leukemia Cell lines

To investigate the differentiation-inducing activity of triciribine (TCN), alone and in combination with all-trans retinoic acid (ATRA), in acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML) cell lines, including ATRA-resistant HL-60-R2.

APL (NB4) and AML (HL-60, K052, HL-60-R2) cell lines were treated with TCN and/or ATRA. Cell proliferation was measured using Cell Count Reagent SF. Differentiation was assessed by quantitative PCR, flow cytometry for surface markers, morphological analysis with Wright-Giemsa staining and nuclear-to-cytoplasmic ratio quantification, and nonspecific esterase staining.

TCN and ATRA each inhibited proliferation, with combination treatment producing a significant additive effect. Expression of differentiation markers, particularly CD11b and CD11c, was enhanced under combined treatment. Morphological analyses revealed cytoplasmic expansion, nuclear indentation, peripheral budding, and vacuole formation, with significantly reduced nuclear-to-cytoplasmic ratios. Nonspecific esterase staining confirmed α-naphthyl butyrate esterase positivity, supporting induction of partial myelomonocytic differentiation in all cell lines, including ATRA-resistant HL-60-R2.

TCN augments the differentiation-inducing activity of ATRA and promotes partial myelomonocytic differentiation, even in ATRA-resistant AML cells. Combination of TCN with established differentiation therapy may provide a strategy to overcome differentiation blockade in AML.