Tanshinone IIA in Acute Promyelocytic Leukemia

Introduction: The prognosis of acute promyelocytic leukemia (APL) has been significantly improved by the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, the utility of these drugs is limited by resistance to ATRA and the side effects of ATO. It has been reported that Tanshinone IIA (Tan IIA), a diterpene quinone isolated from Salvia Miltiorrhiza Bunge, induces apoptosis in the APL cell line, NB4. The effect of Tan IIA on the ATRA-resistant APL cell line (MR2) is unknown. Methods: In this study, the effects of Tan IIA and ATO, alone and in combination, on MR2 cell apoptosis were investigated using transmission electron microscopy, flow cytom-etry and Western blot analyses. Results: Nuclear changes typical of apoptosis were observed in Tan IIA-treated MR2 cells. Apoptosis was shown to be induced in a dose-and time-dependent manner with the activation of caspase-3 resulting in upregulation of tumor necrosis factor-a expression, activation of caspase-8 and alteration in mitochondrial transmembrane potential with release of cytochrome c (cyto-c). Tan IIA and ATO acted synergistically on the induction of MR2 cell apoptosis. Conclusions: These data indicate that Tan IIA may be beneficial in the treatment of ATRA-resistant APL and in combination with ATO for APL therapy in the clinic.