Progress in antitumor research of triptolide and its derivatives

Triptolide is the main bioactive component of Tripterygium wilfordii, which has multiple biological effects including anti-tumor In cooperation with Giovanni capranico laboratory, University of Bologna, Italy, Miao Zehong research group, Li Yuanchao research group and Ding Jian research group of Shanghai Institute of medicine, Chinese Academy of sciences have made phased progress in the research on the antitumor effect and mechanism of triptolide and its derivatives On the basis of clarifying the selective antitumor effect of triptolide derivatives substituted by C14 β - hydroxy group (J Med chem 2009; 52: 5115 – 5123), it was found that triptolide can increase the level of hypoxia inducible factor-1 α (HIF-1 α) but decrease its transcription activity, which is related to its antitumor effect (mol cancer 2010; 9: 268) It has been shown that triptolide can directly bind to XPB, a large subunit of TFIIH, and cause the degradation of rpb1, a large subunit of RNA polymerase II (RNAPII) This cooperative study reveals the molecular basis and significance of triptolide acting on this core target Triptolide decreased rpb1 level closely related to its cytotoxic activity, i.e it blocked RNAPII at the promoter of the gene, reduced the chromatin binding RNAPII at the promoter and exon of the gene, and increased phosphorylation (5-serine) and ubiquitination of the carboxy terminal domain of rpb1 Proteasome inhibitor or Cdk7 inhibitor can reduce the ability of triptolide to degrade rpb1 Therefore, researchers found that triptolide triggered Cdk7 to mediate the degradation of RNAPII, and proposed the general mechanism of triptolide combined with XPB to degrade RNAPII This mechanism can well explain the multiple therapeutic properties of triptolide including its strong antitumor activity (cancer res.2012; doi: 10.1158/0008-5472 Can-12-1006) The researchers were also invited to write a special review of triptolide, systematically summarizing the research progress of structural modification, structure-activity relationship, function and mechanism, and clinical development of triptolide (NAT prod Rep 2012; 29: 457-475).