Abstract
Cell growth and viability are dependent on the function of the multicatalytic proteinase complex (proteasome), a multisubunit particle that affects progression through the mitotic cycle by degradation of cyclins. Exposure of rodent fibroblasts and human lymphoblasts in culture to benzyloxycarbonyl-leucyl-leucyl-phenylalaninal (Z-LLF-CHO), a cell-permeable peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome, resulted in the induction of apoptosis in a rapid, dose-dependent fashion. Fibroblasts transformed with ras and myc, lymphoblasts transformed by c-myc alone, and a Burkitt's lymphoma (BL) cell line that overexpresses c-Myc were up to 40-fold more susceptible to apoptosis than were either primary rodent fibroblasts or immortalized nontransformed human lymphoblasts, respectively. To determine whether such preferential apoptosis could impact upon tumor growth in vivo, toxicological studies were performed in mice with severe combined immunodeficiency and showed that mice tolerated single interscapular doses of Z-LLF-CHO without unacceptable toxicity. Severe combined immuno-deficient mice bearing s.c. BL tumors in the flank were treated interscapularly with Z-LLF-CHO or a comparable dose of the peptidyl alcohol (Z-LLF-OH), which does not induce proteasome inhibition or apoptosis. Single doses of Z-LLF-CHO induced statistically significant (P < 0.0001) early tumor regression and a significant (P < 0.0001) delay in tumor progression. Analysis of tumor specimens revealed increased apoptosis in BL tumors from mice treated with Z-LLF-CHO. These results, showing a 42% tumor growth delay, indicate that proteasome inhibitors have the potential of curbing the growth of a c-myc-related tumor.
Footnotes
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↵1 R. Z. O. was supported in part by a Young Investigator Award from the American Society of Clinical Oncology. C. V. D. is a Scholar of the Leukemia Society of America. This work was also supported in part by NIH Grants T32CA09071 (to R. Z. O.), DK 25377 (to M. O.), and CA 51497 (to C. V. D.).
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↵2 To whom requests for reprints should be addressed, at: Department of Medicine, Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, 22-003 Lineberger Comprehensive Cancer Center, CB 7295, Mason Farm Road, Chapel Hill, NC 27599-7295. Phone: (919) 966-9762; Fax: (919) 966-8212; E-mail: R_Orlowski@med.unc.edu.
- Received May 13, 1998.
- Accepted August 3, 1998.
- ©1998 American Association for Cancer Research.
Volume 58, Issue 19
