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

Abstract

Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-α is limited by its activation of NF- κB and activation of NF-κB is proinflammatory. We have identified a compound called PG490, that is composed of purified triptolide, which induces apoptosis in tumor cells and sensitizes tumor cells to TNFα-induced apoptosis. PG490 potently inhibited TNF-α-induced activation of NF-κB. PG490 also blocked TNFα-mediated induction of c-IAP2 (hiap-1) and c-IAP1 (hiap-2), members of the inhibitor of apoptosis (IAP) family. Interestingly, PG490 did not block DNA binding of NF-κB, but it blocked transactivation of NF-κB. Our identification of a compound that blocks TNF-α-induced activation of NF-κB may enhance the cytotoxicity of TNF-α on tumors in vivo and limit its proinflammatory effects.