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 Park, M.-T. Articles by Lee, S.-J. Search for Related Content PubMed PubMed Citation Articles by Park, M.-T. Articles by Lee, S.-J.

Research Articles: Therapeutics, Targets, and Development

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

¹ Laboratory of Radiation Experimental Therapeutics, ² Laboratory of Radiation Functional Genomics, ³ Laboratory of Tissue Engineering, and ⁴ Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences; and ⁵ Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea

Requests for reprints: Su-Jae Lee, Laboratory of Experimental Therapeutics, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea. Phone: 82-2-970-1324; Fax: 82-2-970-2402. E-mail: sjlee{at}kcch.re.kr

Abstract

Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As₂O₃) enhanced cell death of naturally As₂O₃-resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment–induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As₂O₃ induces synergistic apoptosis in As₂O₃-resistant leukemia cells through the p38 MAPK–mediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As₂O₃ treatment. [Mol Cancer Ther 2007;6(1):82–92]

Grant support: Korea Science and Engineering Foundation and Ministry of Science and Technology, Korean government, through its National Nuclear Technology Program.

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.

Note: M-T. Park and Y-H. Kang contributed equally to this work.

⁶ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 6/14/06; revised 9/28/06; accepted 11/28/06.