Wogonin sensitizes resistant malignant cells to TNFalpha- and TRAIL-induced apoptosis.
TNFalpha has previously been used in anticancer therapy. However, the therapeutic application of TNFalpha was largely limited due to its general toxicity and the fact that it activates the NF-kappaB-family transcription factors, which are proinflammatory and antiapoptotic. To overcome this problem in vitro, specific NF-kappaB inhibitors or transcription or protein synthesis inhibitors such as actinomycin D and cycloheximide are usually used in combination to increase TNFalpha killing of tumor cells. However, these agents also cause harmful side effects in vivo. We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-kappaB activity by shifting TNFalpha-induced free radical .O(2)(-) to a more reduced nonradical product, H(2)O(2), and thereby sensitizes TNFalpha-resistant leukemia cells to TNFalpha-induced apoptosis. Importantly, wogonin does not affect the viability of normal peripheral blood T cells. Wogonin also sensitizes TRAIL-induced apoptosis. Our data suggest a potential use of wogonin as a TNFalpha or TRAIL adjuvant for cancer treatment. Our data also demonstrate how a herbal compound enhances killing of tumor cells with reduced side effects compared with other treatments.
Fas
Stefanie C
SC
Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Baumann
Sven
S
Zhu
Jia Yun
JY
Giaisi
Marco
M
Treiber
Monika K
MK
Mahlknecht
Ulrich
U
Krammer
Peter H
PH
Li-Weber
Min
M
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003513:Cycloheximide / Q000494:pharmacology / Q000627:therapeutic use; D003609:Dactinomycin / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D044950:Flavanones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D004365:Drugs, Chinese Herbal; D044950:Flavanones; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D003609:Dactinomycin; D003513:Cycloheximide; D006861:Hydrogen Peroxide; C085514:wogonin