title: (5R)-5-hydroxytriptolide (LLDT-8), a novel immunosuppressant in clinical trials, exhibits potent antitumor activity via transcription inhibition.
abstract: (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative, is a low-toxicity immunosuppressant in Phase I clinical trials. Here, we demonstrate that LLDT-8 displays broad-spectrum, potent (nanomolar level IC(50)s) antitumor activity, and induces S-phase cell-cycle arrest and apoptosis in vitro. Notably, LLDT-8 effectively overcomes multidrug resistance mediated by P-glycoprotein. In vivo, LLDT-8 demonstrates potent antitumor activity, particularly against human ovarian cancer 3AO and prostate cancer PC-3 xenografts in nude mice. The antitumor activity of LLDT-8 is achieved by virtue of its general inhibition of gene transcription. Our results indicate that LLDT-8 is a novel transcription inhibitor with potential for cancer therapy, particularly for cancers with drug resistance mediated by P-glycoprotein.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Li
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D016196:S Phase / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C509074:5-hydroxytriptolide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004224:Diterpenes; D007166:Immunosuppressive Agents