Figure 4.

Cell suicide as a response to cell stress and chemotherapy – opportunities for use of BH3-only mimetics. Toxins and chemotherapeutic drugs can partially or completely interrupt vital processes causing cell stress (red color). Healthy cells have well-tuned homeostatic mechanisms, and can repair such damage, but if there is sufficient damage, they can trigger the apoptotic mechanism to kill themselves. Tumor cells with higher levels of anti-apoptotic BCL2 family members would resist apoptosis, and be at a selective advantage. A chemotherapeutic drug will be useful if it causes tumor cells to die either by direct toxicity or by inducing apoptosis, as long as it does not cause too many normal cells to die. BH3 mimetic drugs might act alone to cause death of tumor cells with high levels of anti-apoptotic BCL2 family proteins, and might synergize with chemotherapeutic drugs by decreasing their threshold for activation of apoptosis. The therapeutic index would be a function of the strength of the homeostatic mechanisms and the relative dependence on high levels of anti-apoptotic BCL2 family proteins