Trans-Cinnamaldehyde Induces Granulocytic Differentiation and Impairs Survival and Migration of Acute Myeloid Leukemic Cells

Trans-cinnamaldehyde (TCA), the major active component of oil isolated from the stem bark of Cinnamomum cassia traditionally used to treat dyspepsia, gastritis and inflammatory disease world widely, has been shown to inhibit proliferation and promote apoptosis in a number of cancer cells. However, the functional roles TCA plays in hematopoietic system have not been fully investigated. In this study, we show the effects of TCA on acute promyelocytic leukemia (APL) cell line HL60 and primary bone marrow mononuclear cells (BMMNC) as well as bone marrow stromal cells (BMSC) from acute myeloid leukemia (AML) patients. We found that TCA affected HL60 cells in a time-and dose-dependent fashion. Low concentration of TCA (20 μM) arrested HL60 cells at G₀/G₁ phase at 72 h without significant apoptosis. Middle concentration of TCA (60 μM) accumulated HL60 cells at G₂/M at 24 h with increased apoptosis when the treated time was prolonged. Both low and middle concentrations of TCA induced HL60 cells to differentiate toward mature granule cells characterized with up-regulation of CD11b on cells accompanied by decreased c-Myc protein and increased p27 protein. Consistently, the expression and cellular distribution of p16 and Cdc6 were also significantly changed in differentiated HL60 cells treated with TCA. On the other hand, high concentration of TCA (100 μM) rapidly inhibited NF-kappaB activity and induced apoptosis in HL60 cells. Importantly, TCA induced apoptosis of AML CD34⁺ cells and suppressed colony formation of AML BMMNC, while its cytotoxicity on normal BMMNC was minor. In addition, TCA synergized with AraC to kill AML BMMNC and AML CD34⁺ cells. Finally, TCA also decreased CXCR4 expression on HL60 cells, consistent with it ability to depress migration and invasion of HL60 cells induced by rhSDF-1α as well as the adhesion of HL60 cells to AML BMSC. Of note, TCA also impaired survival and SDF-1α secretion of AML BMSC, which may further suppress the interaction of HL60 with AML BMSC. Taken together, our data show that TCA is an effective agent for the treatment of hematopoietic malignancies, not only being the direct inducer of terminal differentiation and apoptosis of acute myeloid leukemic cells, but attenuating the protective effect of AML BMSC on leukemia cells via inhibiting SDF-CXCR4 axis, which highlights the potential of TCA to be a promising therapeutic agent for hematopoietic malignancies treatment.