5. Conclusion
The broad spectrum caspase inhibitor, Q-VD-OPh, provides not only a cost effective, non-toxic, and highly specific means of apoptotic inhibition but also new insight into next generation caspase inhibitors. Our data indicate that the specificity and effectiveness of next generation caspase inhibitors will be significantly enhanced by incorporating conjugated aminoterminal quinolyl and carboxyterminal O-phenoxy groups. A major disadvantage of fluoromethyl ketone and other carboxyterminal-conjugated caspase inhibitors has been the resultant toxicity in vivo which has hampered their use. Future studies examining other amino terminal modifications to 0-phenoxy conjugates to decrease hydrophobicity as well as nonpeptide, selective caspase inhibitors should provide even greater effectiveness. Studies assessing in vivo specificity, clearance, and toxicity of Q-VD-OPh will determine the potential use of this new generation of Ophenoxy caspase inhibitor conjugates as promising new therapeutics.
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7. References
D.R. Plas and CB Thompson, Cell metabolism in the regulation of programmed cell death, Trends Endocrinol Metab. 13, 75–8 (2002).
W.C. Earnshaw, L.M. Martins, S.H. Kaufmann, Mammalian caspases: structure, activation, substrates, and functions during apoptosis, Ann Rev Biochem. 68, 383–424 (1999).
G.S. Salvesen and V.M. Dixit, Caspases: intracellular signaling by proteolysis, Cell 91, 443–446 (1997).
G.M. Cohen, Caspases: the executioners of apoptosis, Biochem. J. 326, 1–16 (1997).
T.L. Brown, S. Patil and P.H. Howe, Analysis of TGF eta-Inducible Apoptosis, In Methods in Molecular Biology —“Transforming growth factor-beta protocols,” P. Howe, ed., (Totowa, NJ: Humana Press) 142, 149–67 (2000).
J.C. Goldstein, N.J. Waterhouse, P. Juin, G.I. Evan, and D.R. Green, The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant, Nat Cell Biol. 2, 156–62 (2000).
X.M. Yin, Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways, Cell Res. 10, 161–7 (2000).
M. Fujino, X.K. Li, Y. Kitazawa, L. Guo, M. Kawasaki, N. Funeshima, T. Amano, and S. Suzuki, Distinct pathways of apoptosis triggered by FTY720, etoposide, and anti-Fas antibody in human T-lymphoma cell line (Jurkat cells), J Pharmacol Exp Ther. 300, 939–45 (2002).
J.D. Robertson, M. Enoksson, M. Suomela, B. Zhivotovsky, S. Orrenius, Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis, J Biol Chem 277, 9803–9 (2002).
T. Nakagawa, H. Zhu, N. Morishima, E. Li, J. Xu, B.A. Yankner, and J. Yuan, Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta, Nature. 403, 98–103 (2000).
R.V. Rao, E. Hermel, S. Castro-Obregon, G. del Rio, L.M. Ellerby, H.M. Ellerby, and D.E. Bredesen, Coupling endoplasmic reticulum stress to the cell death program: Mechanism of caspase activation, J Biol. Chem. 276, 33869–74 (2001).
H. Fischer, U. Koenig, L. Eckhart, E. Tschachler, Human caspase 12 has acquired deleterious mutation. Biochem Biophys Res Commun. May 3;293(2), 722–6 (2002).
P. Schotte, W. Declercq, S. Van Huffel, P. Vandenabeele, and R. Beyaert, Non-specific effects of methyl ketone peptide inhibitors of caspases, FEBS Lett. 442, 117–21 (1999).
C.J. Van Noorden, The history of Z-VAD-FMK, a tool for understanding the significance of caspase inhibition, Acta Histochem. 103, 241–51 (2001).
R. Mischak, ICN/ESP Caspase inhibitors: Applications in vivo and in vitro, ICN Bioconcepts 8, 1–5 (2002).
T.M. Caserta, A.N. Smith, A.D. Gultice, M.A. Reedy, and TL. Brown, Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties, Apoptosis 8, 345–352 (2003).
T.L. Brown, S. Patil, R.K. Basnett, and P.H. Howe, Caspase inhibitor BD-fmk distinguishes transforming growth factor beta-induced apoptosis from growth inhibition, Cell Growth Diff. 9, 869–875 (1998).
T.L. Brown, S. Patil, C.D. Cianci, J.S. Morrow, and P.H. Howe, TGF beta induces caspase 3 independent cleavage of alpha II spectrin (alpha-fodrin) coincident with apoptosis, J. Biol. Chem. 274, 23256–23262 (1999).
S.T. Williams, A.N. Smith, C.D. Cianci, J.S. Morrow, and T.L. Brown, Identification of the primary caspase 3 cleavage site in alpha II spectrin during apoptosis, Apoptosis 8, 353–361 (2003).
S. Patil, G.M. Wildey, T.L. Brown, L. Choy, R. Derynck, and P.H. Howe, Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta-induced growth inhibition and apoptosis, J Biol Chem. 275, 38363–70 (2000).
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Brown, T.L. (2004). Q-VD-OPh, Next Generation Caspase Inhibitor. In: Lauf, P.K., Adragna, N.C. (eds) Cell Volume and Signaling. Advances in Experimental Medicine and Biology, vol 559. Springer, Boston, MA . https://doi.org/10.1007/0-387-23752-6_26
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