Rocaglamide sensitizes leukemic T cells to activation-induced cell death by differential regulation of CD95L and c-FLIP expression.
Drugs with tumor selectivity may have an important benefit in chemotherapies. We have previously shown that Rocaglamide(s), derived from the medicinal plant Aglaia, kills various leukemic cells through the mitochondrial apoptosis pathway with only minor toxicities to normal lymphocytes. Here, we show further that Rocaglamide preferentially promotes activation-induced cell death in malignant T cells by differential regulation of c-FLIP and CD95L expression. Rocaglamide enhances and also prolongs activation-induced JNK activation in malignant T cells leading to downregulation of c-FLIP but upregulation of CD95L expression. We also show that malignant T cells express a significantly higher amount of Bid - the molecular linker that bridges the receptor-mediated to the mitochondria-mediated apoptosis pathway. Conversely, a substantially lower amount of c-FLIP in response to T-cell stimulation compared to normal T cells is observed. This difference may provide a therapeutic window for cancer treatment. The effect of Rocaglamide on sensitization of activation-induced cell death in malignant T cells was further demonstrated in vivo in a mouse model. Our study demonstrates that Rocaglamide may be a potential anticancer drug that simultaneously targets both c-FLIP and CD95L expressions in tumor cells. This study may also provide a new clue to design a more efficient chemotherapy by using a combination of stimuli that engage the receptor-mediated and the mitochondria-mediated death pathway.
Tumorimmunology Program (D030), German Cancer Research Center, D-69120 Heidelberg, Germany.
J Y
JY
Zhu
M
M
Giaisi
R
R
Köhler
W W
WW
Müller
A
A
Mühleisen
P
P
Proksch
P H
PH
Krammer
M
M
Li-Weber
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D001572:Benzofurans; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; C107772:rocaglamide; D048031:JNK Mitogen-Activated Protein Kinases