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Research Articles: Therapeutics, Targets, and Development

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Departments of ¹ Obstetrics and Gynecology and ² Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ³ Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China; and ⁴ Department of Chemistry, Southwestern Oklahoma State University, Weatherford, Oklahoma

Requests for reprints: Doris Benbrook, Department of Obstetrics/Gynecology, University of Oklahoma Health Sciences Center, 975 N.E. 10th St., Room 1372, Oklahoma City, OK 73104. Phone: 405-271-5523; Fax: 405-271-3874. E-mail: doris-benbrook{at}ouhsc.edu

Abstract

Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x_L, and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het–induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent Flex-Het mitochondrial or apoptosis effects. Bcl-2 and Bcl-x_L levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis. [Mol Cancer Ther 2007;6(6):1814–22]

Grant support: Oklahoma IDeA Network for Biomedical Research Excellence and National Cancer Institute grants CA 99197 and CA 106713.

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.

⁵ S.A. Lightfoot, T. Liu, D. Benbrook. Flex-Hets inhibit angiogenesis and induce ischemic necrosis in renal cancer xenografts. Am J Pathol 2007, in preparation.

Received 5/12/06; revised 2/21/07; accepted 4/26/07.

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