Submitted June 15, 2007
Accepted December 5, 2007
Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLC
1- and Ca2+-dependent apoptosis
Sven Baumann, Stefanie C Fas, Marco Giaisi, Wolfgang W Muller, Anette Merling, Karsten Gulow, Lutz Edler, Peter H Krammer, and Min Li-Weber*
Tumorimmunology Program, D030, German Cancer Research Center (DKFZ), Heidelberg, Germany
Bio-statistics Unit, C060, German Cancer Research Center (DKFZ), Heidelberg, Germany
* Corresponding author; email: m.li-weber{at}dkfz-heidelberg.de.
Herbs have successfully been used in traditional Chinese medicine (TCM) for centuries. However, their curative mechanisms remain largely unknown. In this study, we show that Wogonin, derived from the TCM Huang-Qin (Scutellaria baicalensis Georgi), induces apoptosis in malignant T-cells in vitro and suppresses growth of human T-cell leukemia xenografts in vivo. Importantly, Wogonin shows almost no toxicity on T-lymphocytes from healthy donors. Wogonin induces prolonged activation of PLC
1 via H2O2 signaling in malignant T-cells which leads to sustained elevation of cytosolic Ca2+ in malignant but not normal T-cells. Subsequently, a Ca2+ overload leads to disruption of the mitochondrial membrane. The selective effect of Wogonin is due to its differential regulation of the redox status of malignant vs. normal T-cells. In addition, we show that the L-type voltage-dependent Ca2+ channels (VDCC) are involved in the intracellular Ca2+ mobilization in T-cells. Furthermore, we show that malignant T-cells possess elevated amounts of VDCC compared to normal T-cells which further enhance the cytotoxicity of Wogonin for malignant T-cells. Taken together, our data show a therapeutic potential of Wogonin for the treatment of hematologic malignancies.
