A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells
- Eur J Med Chem. 2021 Oct 5:221:113528. doi: 10.1016/j.ejmech.2021.113528.
- 1. Department of Neurosurgery, Affiliated Kunshan Hospital of Jiangsu University, First People's Hospital of Kunshan, Suzhou, 215300, PR China.
- 2. Department of Oncology, The People's Hospital of Funing County in Yancheng City, Yancheng, 224400, Jiang Su, PR China.
- 3. Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, Suzhou, Suzhou, 215021, PR China. Electronic address: [email protected].
- 4. Department of Surgery, Children's Hospital of Soochow University, Suzhou, 215021, PR China.
- 5. Department of Surgery, Children's Hospital of Soochow University, Suzhou, 215021, PR China. Electronic address: [email protected].
Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising Anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 μM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent Apoptosis, caused by Caspase activation, production of Reactive Oxygen Species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma Cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.