RESUMEN
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 and the Top2 inhibitor etoposide, respectively. Consistently, tanshinone-1 and its derivatives induced DNA double-strand breaks, G2/M arrest and apoptosis. Unexpectedly, the derivatives demonstrated different p53-dependency in inducing both cell cycle arrest and apoptosis. S222 showed no obvious p53-dependency. In contrast, S439 induced more G2/M arrest in p53-proficient cells than in p53-deficient cells while its apoptotic induction was the opposite. However, their proliferative inhibition was independent of the p53 status. Due to their structures different from the known Top1, Top2 and dual Top1/2 inhibitors, our results indicate that tanshinone-1 and its derivatives are a new type of dual Top1/2 inhibitors.
Asunto(s)
Abietanos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Genes p53/efectos de los fármacos , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/farmacología , Células A549 , Abietanos/química , Apoptosis/fisiología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/fisiología , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G2 del Ciclo Celular/fisiología , Genes p53/fisiología , Células HCT116 , Humanos , Células K562 , Células MCF-7 , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 µM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.