Sensitization of AIDS Kaposi's sarcoma cells to Apo-2 ligand-induced apoptosis by actinomycin D

Kaposi's sarcoma (KS) is the most frequent malignancy associated with HIV i nfection (AIDS-KS), a complication that leads to high mortality and morbidi ty. AIDS-KS cells are resistant to killing by chemotherapeutic drugs/NK cel ls and Fat-induced apoptosis, suggesting that the acquisition of anti-apopt otic characteristics by AIDS-KS cells may contribute to their prolonged sur vival. Apo-2 ligand (Apo-2L)/TNF-related apoptosis-inducing ligand, a new m ember of the TNF family has been identified as an apoptosis-inducing molecu le, In this study we examined the sensitivity of 10 different AIDS-KS isola tes to Apo-2L-mediated cytotoxicity. AIDS-KS cells were relatively resistan t to Apo-2L; however, Apo-2L and actinomycin D (Act D) used in combination synergistically potentiated the induction of cell death in nine of the 10 i solates, Apo-2L induced apoptosis in >80% of AIDS-KS cells pretreated with Act D, The caspase inhibitors, zIETD-fmk and zDEVD-fmk, inhibited apoptosis in AIDS-KS by sApo-2L, suggesting that caspase 3-like and caspase 8 or 10 activities are essential for Apo-2L-mediated apoptosis, Act D treatment of AIDS-KS cells markedly and selectively down-regulated Bcl-x(L), expression. while the expressions of decoy receptors 1 and 2, Bas, cellular FLICE (Fas -associated death domain protein-like IL-1-converting enzyme) inhibitory pr otein, FADD (Fas-associated death domain protein), procaspase 8, and p53 we re not effected. These findings suggest the possible involvement of Bcl-x(L ) in Act D-induced sensitization of AIDS-KS cells to Apo-2L-mediated apopto sis, Furthermore, Act D did not sensitize PBMC or fibroblast cells to Apo-2 L. Thus, Apo-2L and Act D used in combination may be of therapeutic value i n the treatment of AIDS-KS.