DMAKO-20 as a New Multitarget Anticancer Prodrug Activated by the Tumor Specific CYP1B1 Enzyme
DMAKO-20 as a New Multitarget Anticancer Prodrug Activated by the Tumor Specific CYP1B1 Enzyme
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DMAKO-20 作为一种由肿瘤特异性 CYP1B1 酶激活的新型多靶点抗癌前药
DOI：
10.1021/acs.molpharmaceut.8b01062
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发表时间：
2019-01-01
影响因子：
4.9
通讯作者：
Li，Shaoshun
中科院分区：
文献类型：
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作者：
Cui，Jiahua;Zhang，Xu;Li，Shaoshun
为了降低天然紫草素、紫草素及其合成类似物的普遍毒性并增强这些化疗药物对癌细胞的选择性，设计、合成了一种新型5,8-二甲基紫草素肟衍生物（DMAKO-20），并评估了其强大的体外和体内抗肿瘤活性。它对 HCT-15、HCT-116 和 K562 细胞具有强效生长抑制作用 (IC50< 1 μM)，对 MDA-MB-231、HepG2、PANC、Bel7402 和 MGC803 癌细胞具有中等抗增殖活性 (IC50< 10 μM)，并且对人类正常 VEC 和 HSF 细胞无毒。 体内功效研究表明DMAKO-20（每隔一天 10 mg/kg，静脉注射，14 天内 8 次）导致 HCT-15 异种移植物体积减少 59.3%。它与有毒的抗代谢物 5-FU 一样有效，但在小鼠中既没有显示出毒性，也没有导致死亡。机理研究表明，DMAKO-20 经历了肿瘤特异性 CYP1B1 催化的生物活化，产生一氧化氮和活性萘醌单肟，从而表现出联合抗癌作用。被定义为“癌细胞内特定酶激活的多靶点抗癌前药”的代表。产生的活性代谢物通过直接亲核烷基化发挥抗癌作用，并通过激活线粒体途径诱导癌细胞凋亡。 DMAKO-20的发现及其分子机制的阐明可能为克服当前化疗药物的非选择性毒性提供新策略。
To reduce the pervasive toxicity of natural shikonin, alkannin, and their synthetic analogues and to enhance the selectivity of these chemotherapeutics toward cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized, and evaluated for its strong antitumor activity bothin vitroandin vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116, and K562 cells (IC50< 1 μM), moderate antiproliferative activity toward MDA-MB-231, HepG2, PANC, Bel7402, and MGC803 cancer cells (IC50< 10 μM), and was nontoxic to the human normal VEC and HSF cells.In vivoefficacy studies demonstrated that DMAKO-20 (10 mg/kg,i.v. on every the other day, 8 times in 14 days) resulted in 59.3% reduction in HCT-15 xenograft volume. It was as effective as the toxic antimetabolite 5-FU but revealed neither toxicity nor death in mice. The mechanistic investigations indicated that DMAKO-20 underwent the tumor-specific CYP1B1-catalyzed bioactivation to afford nitric oxide and active naphthoquinone mono-oximes, which exhibited combined anticancer effects. It was defined as a representative of the “Multi-target Anticancer Prodrugs Activated by Specific Enzymes in cancer cells”. The produced active metabolites exerted anticancer effects by the direct nucleophilic alkylation and the induction of the apoptosis of cancer cells through activation of the mitochondrial pathway. The discovery of DMAKO-20 and the illustration of its molecular mechanisms may provide a new strategy to overcome the nonselective toxicity of the current chemotherapeutics.