Unclear to me what is meant by (-)-gossypol. Does the double negative mean just gossypol, or what? I've seen this in genetic studies, where it means the gene in question was entirely (both alleles) knocked out, but I don't understand it in this context. Illumination appreciated.
It is not minus minus but minus hyphen.
(–)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-XL-mediated apoptosis resistance
Christopher L. Oliver1, Michelle B. Miranda2, Sanjeev Shangary2, Stephanie Land3, Shaomeng Wang5 and Daniel E. Johnson2,4
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-XL, 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-XL 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-XL 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-XL (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-XL 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. |
