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 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-alpha is limited by its activation of NF-kappaB and activation of NF-kappaB 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 TNF-alpha-induced apoptosis. PG490 potently inhibited TNF-alpha-induced activation of NF-kappaB. PG490 also blocked TNF-alpha-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-kappaB, but it blocked transactivation of NF-kappaB. Our identification of a compound that blocks TNF-alpha-induced activation of NF-kappaB may enhance the cytotoxicity of TNF-alpha on tumors in vivo and limit its proinflammatory effects.
Lee
K Y
KY
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Chang
W
W
Qiu
D
D
Kao
P N
PN
Rosen
G D
GD
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D017931:DNA Primers; D004224:Diterpenes / Q000494:pharmacology*; D004357:Drug Synergism; D004852:Epoxy Compounds; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000473:pathology; D010616:Phenanthrenes; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D004224:Diterpenes; D004852:Epoxy Compounds; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D010616:Phenanthrenes; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C001899:triptolide; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases