A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells
| Autor: | Qian-wei Xiong, Lei Shi, Li-li Gao, Zhou-rui Ma, Shi-zhong Cai |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Curcumin
Cell Survival Thioredoxin reductase Antineoplastic Agents Apoptosis Mitochondrion 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Glioma Drug Discovery Tumor Cells Cultured medicine Animals Humans Cytotoxicity Cell Proliferation 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Reactive oxygen species Dose-Response Relationship Drug Molecular Structure Brain Neoplasms 010405 organic chemistry Chemistry Organic Chemistry General Medicine medicine.disease Mitochondria Rats 0104 chemical sciences Tumor progression Cancer research Drug Screening Assays Antitumor |
| Zdroj: | European Journal of Medicinal Chemistry. 221:113528 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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