This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xia, L. Articles by Jing, Y. Search for Related Content PubMed PubMed Citation Articles by Xia, L. Articles by Jing, Y.

¹ Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York and ² Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China

Requests for reprints: Yongkui Jing, Division of Hematology/Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6547. Phone: 212-241-6775; Fax: 212-996-5787. E-mail: yongkui.jing{at}mssm.edu

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of -boswellic acid acetate and ß-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 µg/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-X_L were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate–induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.

Key Words: Boswellic acid acetate • Apoptosis • Myeloid leukemia • Caspases • Death receptors

Grant support: G&P Foundation for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/ 4/03; revised 12/29/04; accepted 1/ 5/05.