Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor.
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 immunodeficient 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.
Orlowski
R Z
RZ
The Johns Hopkins Oncology Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. R_Orlowski@med.unc.edu
Eswara
J R
JR
Lafond-Walker
A
A
Grever
M R
MR
Orlowski
M
M
Dang
C V
CV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts; D006801:Humans; D020287:In Situ Nick-End Labeling; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009097:Multienzyme Complexes / Q000378:metabolism*; D009842:Oligopeptides / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011916:Rats, Inbred F344; D015842:Serine Proteinase Inhibitors / Q000633:toxicity*
D009097:Multienzyme Complexes; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C077180:N-benzyloxycarbonyl-leucyl-leucyl-phenylalaninal; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex