DMAKO-20 as a New Multitarget Anticancer Prodrug Activated by the Tumor Specific CYP1B1 Enzyme

• DOI: 10.1021/acs.molpharmaceut.8b01062
• Publication Date: 2018-11-27T22:02:50Z
• Authors: Jiahua Cui; Xu Zhang; Guang Huang; Qijing Zhang; Jinyun Dong; Gege Sun; Qingqing Meng; Shaoshun Li
• Keywords: 0301 basic medicine; Antineoplastic Agents; Apoptosis; Hep G2 Cells; HCT116 Cells; Xenograft Model Antitumor Assays; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Cytochrome P-450 CYP1B1; Animals; Humans; Prodrugs; Drug Screening Assays, Antitumor; K562 Cells; Cell Proliferation; Naphthoquinones

To reduce the pervasive toxicity of natural shikonin, alkannin, and their synthetic analogues to enhance selectivity these chemotherapeutics toward cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized, evaluated for its strong antitumor activity both in vitro vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116, K562 cells (IC50 < 1 μM), moderate antiproliferative MDA-MB-231, HepG2, PANC, Bel7402, MGC803 10 nontoxic human normal VEC HSF cells. In vivo efficacy studies demonstrated that DMAKO-20 (10 mg/kg, i.v. on every other day, 8 times 14 days) resulted 59.3% reduction HCT-15 xenograft volume. as effective toxic antimetabolite 5-FU but revealed neither nor death mice. The mechanistic investigations indicated underwent tumor-specific CYP1B1-catalyzed bioactivation afford nitric oxide active naphthoquinone mono-oximes, which exhibited combined anticancer effects. defined representative "Multi-target Anticancer Prodrugs Activated by Specific Enzymes cells". produced metabolites exerted direct nucleophilic alkylation induction apoptosis through activation mitochondrial pathway. discovery illustration molecular mechanisms may provide new strategy overcome nonselective current chemotherapeutics.