Abstract
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 invitro 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 U251cells with an IC50 of 0.42μM. 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 invitro and invivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.
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