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Research Articles: Therapeutics, Targets, and Development

Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor

¹ Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Hoshi University and ² Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Requests for reprints: Tadashi Yoshida, Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawaku, Tokyo 142-8501, Japan. Phone: 81-3-5498-5618; Fax: 81-3-5498-5916. E-mail: tyoshida{at}hoshi.ac.jp

Abstract

Emodin is an active component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L. Here, we show that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6–induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1–overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. In conclusion, emodin inhibits interleukin-6–induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, our results show emodin as a new potent anticancer agent for the treatment of multiple myeloma patients. [Mol Cancer Ther 2007;6(3):987–94]

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Note: A. Muto and M. Hori contributed equally to this work.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/ 2/06; revised 12/10/06; accepted 1/31/07.