Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLCgamma1- and Ca2+-dependent apoptosis.
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 PLCgamma1 via H(2)O(2) signaling in malignant T cells, which leads to sustained elevation of cytosolic Ca(2+) in malignant but not normal T cells. Subsequently, a Ca(2+) 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 Ca(2+) channels are involved in the intracellular Ca(2+) mobilization in T cells. Furthermore, we show that malignant T cells possess elevated amounts of voltage-dependent Ca(2+) 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.
Baumann
Sven
S
Tumorimmunology Program (D030), German Cancer Research Center, Heidelberg, Germany.
Fas
Stefanie C
SC
Giaisi
Marco
M
Müller
Wolfgang W
WW
Merling
Anette
A
Gülow
Karsten
K
Edler
Lutz
L
Krammer
Peter H
PH
Li-Weber
Min
M
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal; D004790:Enzyme Induction; D044950:Flavanones / Q000633:toxicity*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D051966:Phospholipase C gamma / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology
D004365:Drugs, Chinese Herbal; D044950:Flavanones; D051966:Phospholipase C gamma; C085514:wogonin; D002118:Calcium