On Jan 11th , 2010, Beijing,“Anticancer molecular mechanisms of the novel inhibitor of topoisomerase II, salvicine” won the 2nd prize of State Nature Science award in the State Scientific and Technological Award Congress . The study was completed by Dr.Jian Ding, Zehong Miao, Linghua Meng, Jinsheng Zhang and Chen Qing of Shanghai Institute of Materia Medica.

　　DNA topoisomerase II (Topo II) is a well-recognized chemotherapeutic target and its clinically used inhibitors such as adriamycin are recommended as a first-line treatment option for several cancer types. However, these drugs bear intolerable toxicities, especially bone marrow suppression. Other defects also include the generation of drug resistance and limited efficacy against metastatic tumors. Researchers initially extracted the anticancer lead compound, 4,5-seco-5,10-friedoabieta-3,5(10), 6,8,13-pentaene-ll,12-dione, from the Chinese traditional medicinal herb Salvia prionitis. Structural optimization of the lead compound resulted in the discovery of Salvicine (SAL), a structurally modified diterpenoid quinone with potent anticancer activity.

　　In the study, the molecular mechanisms of the anticancer activity of SAL were systematically studied. SAL was revealed to be a multi-targeted anticancer drug with Topo II as its primary cellular target. The primary discoveries throughout this project are summarized as follows: 1) SAL is a non-DNA intercalative Topo II inhibitor with a mode of action different from classical Topo II inhibitors. Specifically, SAL promotes the non-covalent binding of Topo II to DNA and inhibits the pre- and post-strand Topo II-mediated DNA religation without interfering with the forward cleavage steps. Moreover, SAL binds to the ATPase domain of human Topo IIa with high affinity and inhibits the activity of Topo II through competition with ATP. 2) SAL induces gene specific damage and inhibits DNA repair. SAL generates significant amounts of reactive oxygen species (ROS) in tumor cells, which results in Topo II inhibition and DNA double strand breaks. Preferential damage has been observed in the P2 promoter region of the oncogene c-myc, resulting in down-regulation of c-myc transcription. In addition, SAL reduces the kinase activity and the protein level of the catalytic subunit of DNA-PK, which is a critical component in the non-homologous end joining (NHEJ) pathway. 3) SAL demonstrates anti-multidrug resistance (MDR) activity through the activation of the transcription factor c-Jun, which is a critical factor in the repression of mdr-1 gene expression. 4) SAL inactivates b1 integrin function via ROS generation and abrogates the RhoC-dependent signaling pathway, which collectively contribute to its anti-metastatic activity. 5) SAL interferes with the telomere system by down-regulating the activity of telomerase and the protein level of telomere repeat binding factor, as well as inducing telomere damage and erosion.

　　Phase I clinical trials demonstrated that SAL was well tolerated. Initial curative effect of SAL was observed in 16 cases of cancer patients. At present, SAL is undergoing its Phase II clinical trials.