PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells

Progress in the treatment of solid tumors has been slow and sporadic. The e fficacy of conventional chemotherapy in solid tumors is limited because tum ors frequently have mutations in the p53 gene. Also, chemotherapy only kill s rapidly dividing cells. Members of the tumor necrosis factor (TNF) family , however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-alpha is limited by its activation of NF-kappa B a nd activation of NF-kappa B is proinflammatory, We have identified a compou nd called PG490, that is composed of purified triptolide, which induces apo ptosis in tumor cells and sensitizes tumor cells to TNF-alpha-induced apopt osis, PG490 potently inhibited TNF-alpha-induced activation of NF-kappa B, PG490 also blocked TNF-alpha-mediated induction of c-IAP2 (hiap-1) and c-IA P1 (hiap-2), members of the inhibitor of apoptosis (IAP) family, interestin gly, PG490 did not block DNA binding of NF-kappa B, but it blocked transact ivation of NF-kappa B, Our identification of a compound that blocks TNF-alp ha-induced activation of NP-kappa B may enhance the cytotoxicity of TNF-alp ha on tumors in vivo and limit its proinflammatory effects.