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 Blood, 15 February 2008, Vol. 111, No. 4, pp. 2354-2363.
Prepublished online as a Blood First Edition Paper on December 10, 2007; DOI 10.1182/blood-2007-06-096198.

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NEOPLASIA

Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLC{gamma}1- and Ca2+-dependent apoptosis

Sven Baumann1, Stefanie C. Fas1, Marco Giaisi1, Wolfgang W. Müller1, Anette Merling1, Karsten Gülow1, Lutz Edler2, Peter H. Krammer1, and Min Li-Weber1

1 Tumorimmunology Program (D030) and 2 Bio-statistics Unit (C060), German Cancer Research Center, Heidelberg, Germany

Herbs have successfully been used in traditional Chinese medicine for centuries. However, their curative mechanisms remain largely unknown. In this study, we show that Wogonin, derived from the traditional Chinese medicine 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{gamma}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 versus normal T cells. In addition, we show that the L-type voltage-dependent Ca2+ channels are involved in the intracellular Ca2+ mobilization in T cells. Furthermore, we show that malignant T cells possess elevated amounts of voltage-dependent Ca2+ channels compared with 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.


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