1′-Acetoxychavicol acetate induces apoptosis of myeloma cells via induction of TRAIL

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Abstract

A component of a traditional Thai condiment, 1′-acetoxychavicol acetate (ACA), is a natural compound, and it is obtained from rhizomes of the ethno-medicinal plant Languas galanga (Zingiberaceae). Our previous studies showed that ACA dramatically inhibited cellular growth of multiple myeloma cells in vivo and in vitro through the induction of apoptosis in association with the activation of caspase-8, inactivation of NF-κB, and down-regulation of anti-apoptotic proteins. Subsequently, we investigated the detailed apoptotic pathway of ACA and further demonstrated that ACA up-regulates the expression of both TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) and TRAIL receptor death receptor 5 (DR5). In addition, TRAIL/R-Fc chimera neutralizes the ACA-induced apoptosis. These results suggest that the death signaling of TRAIL is involved in the ACA-induced apoptosis of myeloma cells, and provide a rationale for the induction of TRAIL/Apo2L by ACA, which could potentially be used as a novel therapeutic agent in patients with multiple myeloma.

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Materials and methods

Cells. Various multiple myeloma cell lines including RPMI8226, IM-9, and U266 cells (obtained from the Japanese Cancer Research Resources Bank, Tokyo, Japan) were maintained in RPMI 1640 medium (Gibco-BRL, Gaithersburg, MD) with 10% FBS (Gibco-BRL), 100 U/ml penicillin, and 100 mg/ml streptomycin in a humidified atmosphere with 5% CO2. Bone marrow samples were obtained from patients with multiple myeloma and healthy volunteers, who provided written informed consent, according to the appropriate

ACA selectively induces the apoptosis of multiple myeloma cells dependent on caspase pathway

We previously demonstrated that ACA induces apoptosis of various myeloma cell lines (RPMI8226, U266, and IM-9), as well as cells from freshly isolated samples obtained from patients with multiple myeloma in dose- and time-dependent manners [7]. ACA-induced apoptosis in myeloma cells has been assessed in terms of both morphologic changes including condensed chromatin and fragmented nuclei with apoptotic bodies and the presence of DNA ladder formation [7]. In the present study, treatment of

Discussion

In a previous study, we reported that a traditional Asian condiment, ACA, induced apoptosis via the inhibition of NF-κB activity in human myeloma cell lines, as well as in cells from freshly obtained samples from patients with multiple myeloma [7]. In this study, we demonstrated that ACA-induced apoptosis in multiple myeloma cell line and in primary cells from patients in association with the induction of TRAIL and TRAIL receptor DR5. Moreover, a TRAIL/R-Fc chimera dramatically attenuated

Acknowledgments

We thank Ms. Kaori Saito for her excellent technical assistance. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Takeda Science Foundation; and the Mitsubishi Pharma Research Foundation.

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