EVIDENCE AGAINST THE HYPOTHESIS THAT BCL-2 INHIBITS APOPTOSIS THROUGHAN ANTIOXIDANT EFFECT

We contrasted possible protection against apoptosis afforded by either BCL-2 expression or anti-oxidant inhibitors in the same tumor target challenged by two distinct triggers of apoptosis. Exposure of L929 fib roblasts to tumor necrosis factor (TN Fl or etoposide (VP-16) induced apoptotic death with similar kinetics. Enforced expression of BCL-2 si gnificantly protected against apoptosis induced by VP-16 but had no ef fect against TNF-induced apoptosis. In contrast, the anti-oxidants des ferrioxamine, butylated hydroxyanisol and N-acetyl cysteine all inhibi ted TNF-induced apoptosis in a concentration-dependent fashion. Althou gh exposure to VP-16 resulted in a significant generation of intracell ular oxyradicals, the above three anti-oxidant inhibitors had no effec t on VP-16-induced apoptotic death. Interestingly, enforced expression of BCL-2 also inhibited the ability of VP-16 to generate oxy-radicals and to depress intracellular glutathione levels. These results indica te that BCL-2 can exert anti-oxidant effects but argue against the hyp othesis that these effects are critical to its protection against apop tosis.