New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis.

New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis. Biochem Pharmacol. 2018 May 10;: Authors: Tian QT, Ding CY, Song SS, Wang YQ, Zhang A, Miao ZH Abstract Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). With significantly improved water solubility, S222 and S439 displayed 12- and 14-times more potent proliferative inhibition than their parent tanshinone-1 in a panel of 15 cancer cell lines. Both retained tanshinone-1's anti-MDR and anti-angiogenesis properties and its capability to reduce the phosphorylation of Stat3 at Tyr705 with apparently enhanced efficacy and in these regards, S439 was also slightly more potent than S222. Both derivatives and tanshinone-1 directly inhibited Top1 and Top2 at molecular and cellular levels; the derivatives displayed similar potency but both were more potent than tanshinone-1. The inhibition of S222 and S439 on Top1 and Top2 was also more potent than that of the Top1 inhibitor hydroxylcamptothecin ...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research