Methods and compositions for inducing apoptosis by stimulating er stress

Abstract

The present invention provides a method for inducing apoptosis in selected cells by aggravating ER-stress. The aggravation of ER-stress is achieved in a specific manner by inhibiting SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase), leading to elevated level of cytoplasmic calcium concentration, yet without inhibiting the activity of COX-2 (cyclooxygenase-2) or triggering the release of histamine. Induction of apoptosis may be enhanced by first inducing or further aggravating ER-stress through inhibition of proteasome or proteases. Also provided are compounds and compositions useful as ER-stress aggravating agents, methods for screening, selecting, identifying and designing the same and methods for treating diseased conditions by inducing apoptosis through specific and selective aggravation of ER-stress.

1 . A method of inducing or aggravating stress in a cell's endoplasmic reticulum (ER) to trigger apoptosis, comprising:
 inhibiting SERCA activity selectively in said cell without inhibiting COX-2 activity; and   elevating the expression of CHOP in said cell,   wherein, the combination of inhibiting SERCA activity and elevating CHOP expression results in a condition favorable for initiation of apoptosis in the cell.   
     
     
         2 - 43 . (canceled)