Apoptosis therapeutic inhibition

Dorai, T., Cao, Y.C., Dorai, B., Buttyan R., and Katz, A.E., Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo, Prostate, M, 293, 2001. 

Lapachol (95, from the lapacho tree, genus Tabebuia, family of the catalpa trees, Bignoniaceae) and its analogues show very broad therapeutic capabilities , including activity against cancer which results in apoptosis and inhibition in metastasis, antimicrobial, antifungal, antimalarial and other activities . However, clinical application of lapachol is limited by its high toxicity. Lapachol forms complexes with many metal ions. 

Bonavida, B., Baritaki, S., Huerta-Yepez, S., Vega, M. I., Chatteijee, D., and Yeung, K. (2008). Novel therapeutic applications of nitric oxide donors in cancer Roles in chemo- and immunosensitization to apoptosis and inhibition of metastases. Nitric Oxide 19,152-157. 

Bonavida, B., Baritaki, S., Huerta-Yepez, S., Vega, M.I., Chatteijee, D., and Yeung, K. (2008). Novel therapeutic applications of nitric oxide donors in cancer roles in chemo- and immunosensitization to apoptosis and inhibition of metastases. Nitric Oxide 19,152-157. Brilli, R.J., Rrafte-Jacobs, B., Smith, D.J., Roselle, D., Passerini, D., Vromen, A., Moore, L., Szabo, C. and Salzman, A.L. (1997). Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces pulmonary hypertension. J. Appl. Physiol. 83.1968-1975. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

De Schepper, S., Bmwiere, H., Verhulst, T., Steller, U., Andries, L., Wouters, W. et al. (2003) Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin. The Journal of Pharmacology and Experimental Therapeutics, 304, 881-888. 

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