Rocaglamide sensitizes leukemic T cells to activation-induced cell death by differential regulation of CD95L and c-FLIP expression

Abstract

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 mitochondriamediated death pathway. Cell Death and Differentiation (2009) 16, 1289-1299 doi:10.1038/cdd.2009 published online 17 April 2009 Acute lymphocytic leukemia (ALL) comprises approximately 25% of acute leukemia cases, of which two-third occur in children. Although the cure rates of childhood ALL are relatively high (approximately 85%), 1 the cure rates of adult ALL are poor with only 34-57% in patients below the age of 30 years, 15-17% above the age of 50 years and less than 5% over 60 years of age.

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

“…9 Roc has also been shown to inhibit tumor growth in vivo in mouse tumor models with no toxicity to the liver evaluated by glutamate pyruvate transaminase activity and also no body weight loss. 8,11,15,42 In this study, we show that Roc-A could induce an ATM/ATR-response in many types of cancer cell lines (Fig. 5h).…”

“…9,15 However, whether Roc-A also preferentially inhibits cell-cycle progression in tumor cells has not been examined. To investigate this question peripheral blood T lymphocytes were isolated from healthy donors.…”

Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression

“…Recently, we have shown that Roc suppresses activation-induced expression of c-FLIP in leukemic T cells at the transcriptional level by downregulation of NF-AT activity. 27 In that study, we noticed that the basal level of c-FLIP expression (without activation) was also reduced upon Roc treatment. Thus, we asked whether Roc can sensitize ATL cells to receptor-mediated apoptosis through suppression of c-FLIP expression.…”

“…26 Recently, in vitro and an in vivo mouse T-cell leukemia model, we showed high toxicity to tumor cells and only minor toxicity towards normal cells, e.g., activated T cells. 26,27 Toxicity and cell death is mediated through suppression of c-FLIP expression at the transcriptional level by blocking NF-AT activation. 27 Here, we further investigated whether Roc inhibits c-FLIP expression by additional mechanisms and whether it can be used as a sensitizer of receptor-mediated apoptosis.…”

“…26,27 Toxicity and cell death is mediated through suppression of c-FLIP expression at the transcriptional level by blocking NF-AT activation. 27 Here, we further investigated whether Roc inhibits c-FLIP expression by additional mechanisms and whether it can be used as a sensitizer of receptor-mediated apoptosis. We show that Roc sensitizes resistant ATL cells to receptor (TRAIL-R1/2)-mediated apoptosis by translational suppression of c-FLIP through inactivation of the translation initiation factor 4E (eIF4E).…”