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Unsymmetrically Substituted Polyamine Analogue Induces Caspase-independent Programmed Cell Death in Bcl-2-Overexpressing Cells¹

The Oncology Center Research Laboratories, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [H. C. H., R. A. C.]; Division of Toxicological Sciences, Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205 [H. C. H., R. A. C.]; and Wayne State University, Detroit, Michigan 48202 [P. M. W.]

The polyamine analogue, N¹-ethyl-N¹¹-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm)-induced programmed cell death in NCI H157 cells is accompanied by cytochrome c release, the loss of mitochondrial membrane potential, activation of caspase-3, caspase-mediated poly(ADP-ribose) polymerase cleavage, G₂-M arrest, and DNA and nuclear fragmentation. Overexpression of Bcl-2 completely inhibits CHENSpm-induced cytochrome c release, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. However, Bcl-2 does not abrogate CHENSpm-induced programmed cell death. These results suggest that although cytochrome c release and activation of the caspase-3 protease cascade contribute to the rapid and efficient execution of apoptosis, a caspase cascade-independent pathway also exists and can be activated by CHENSpm treatment.

¹ This work was supported in part by Grants ES07141, CA57545, CA63552, CA58184, and CA51085.

² To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center Research Laboratories, 424 North Bond St., Baltimore, MD 21231. Phone: (410) 955-8580; Fax: (410) 614-9884; E-mail: casero@welchlink.welch.jhu.edu.

Received 3/13/98. Accepted 4/30/98.

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