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Departments of ¹ Otolaryngology, ² Medicine, ³ Biostatistics, and ⁴ Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania and ⁵ Departments of Internal Medicine and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints:Christopher L. Oliver, Department of Otolaryngology University of Pittsburgh Eye and Ear, 200 Lothrop Street, Suite 500 Pittsburgh, PA 15213-2546. Phone: 412-647-2110; Fax: 412-647-2080. E-mail: olivercl{at}msx.upmc.edu

Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X_L, contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, was initially investigated as a contraceptive agent, but subsequently has been shown to possess anticancer properties in vitro and in vivo. Recently gossypol has been found to bind to Bcl-X_L and, with less affinity, to Bcl-2. Here we investigate the ability of the (–) enantiomer of gossypol, (–)-gossypol, to overcome the apoptosis resistance conferred by Bcl-2 or Bcl-X_L overexpression in Jurkat T leukemia cells. (–)-Gossypol potently induced cell death in Jurkat cells overexpressing Bcl-2 (IC₅₀, 18.1 ± 2.6 µmol/L) or Bcl-X_L (IC₅₀, 22.9 ± 3.7 µmol/L). Vector-transfected control cells were also potently killed by (–)-gossypol (IC₅₀, 7.0 ± 2.7 µmol/L). By contrast, the chemotherapy drug etoposide only induced efficient killing of vector-transfected cells (IC₅₀, 9.6 ± 2.3µmol/L). Additionally, (–)-gossypol was more efficient than etoposide at inducing caspase-3 activation and phosphatidylserine externalization in the setting of Bcl-2 or Bcl-X_L overexpression. (–)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial-mediated apoptotic mechanism. Moreover, (–)-gossypol treatment of isolated mitochondria purified from Bcl-2-overexpressing cells also resulted in cytochrome c release, indicating a possible direct action on Bcl-2 present in the mitochondrial outer membrane. Taken together, these results suggest that (–)-gossypol is a potent and novel therapeutic able to overcome apoptosis resistance by specifically targeting the activity of antiapoptotic Bcl-2 family members. (–)-Gossypol may be a promising new agent to treat malignancies that are resistant to conventional therapies.

Key Words: Bcl-2 • Bcl-X_L • Apoptosis • Gossypol • Drug resistance

Grant support: NIH grants RO1 CA86980 (D.E Johnson), University of Pittsburgh Oral Cancer Center Pilot Project Grant (D.E. Johnson), DOD Breast Cancer Program Idea Grant BC000914 (s. Wang), Komen Foundation grant BCTR0201763 (S. Wang, Co-P.I., Dajun Yang, P.I.), and American Academy of Otolaryngology Resident Research Grant (C.L. Oliver)

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.

⁶ S. Wang, unpublished observations.

Received 6/21/04; revised 9/17/04; accepted 3/11/04.

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