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Crosstalk between Fisetin-induced Apoptosis and Autophagy in Human Oral Squamous Cell Carcinoma

oral squamous cell carcinoma fisetin apoptosis autophagy

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#1 Engadin

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Posted 26 April 2019 - 05:44 PM


Fisetin (3,3-,4-,7-tetrahydroxyflavone), a naturally occurring flavonoid, has antioxidant, anti-inflammatory, and anticancer effects. Oral squamous cell carcinoma (OSCC) has a 5-year survival rate lower than that of most other carcinomas, and can create functional and aesthetic problems for the patient. New therapies for OSCC are necessary, and treatment using plant-derived natural substances has recently become a trend. It has been suggested that autophagy may play an important role in cancer therapy. Several studies demonstrated that autophagy inhibition enhances apoptotic cell death. Therefore, autophagy inhibition might be a promising therapeutic method against OSCC. Our results showed that fisetin induced apoptotic cell death in human tongue squamous cell line Ca9-22 could be enhanced by inhibition of autophagy. Thus, autophagy process in fisetin treated OSCC might presumed to play a role of pro-survival. The combination of fisetin and an effective autophagy inhibitor could be a potentially adjuvant and useful treatment for oral cancer.



Head and neck malignancies constitute approximately 5% of human malignancies 1. Almost 95% of head and neck cancers are oral squamous cell carcinoma (OSCC), affecting nearly 500,000 individuals each year 23. The classical treatments for OSCC are surgery, radiotherapy, and/or chemotherapy 4. The clinical characteristics of OSCC, including carcinogenesis, development, progression, invasion, and metastasis, have not yet been elucidated 5, and this malignancy is difficult to cure despite aggressive therapies 6. Therefore, new therapies against OSCC are necessary, and treatment using plant-derived natural substances has recently become a trend.


Fisetin (3,3-,4-,7-tetrahydroxyflavone) is a naturally occurring flavonoid commonly found in fruits and vegetables, such as apples, grapes, strawberries, cucumbers, and onions 78. Fisetin has antioxidative and anti-inflammatory effects 9. Recently, its anticancer potential has been explored, making it a promising agent for prevention and therapy of various cancers, including prostate, colon, and breast 10-12. Fisetin interacts with the cell by binding to and interacting with various molecular targets; for example, it disrupts Wnt, mTOR, and NF-κB signaling, resulting in cell-cycle arrest and preventing invasion and migration of cancer cells 13.

The three main features of programmed cell death (PCD) are apoptosis, autophagy, and programmed necrosis, which are easily distinguished by their morphological differences. PCD affects the balance between cell survival and death, and plays a key role in the ultimate outcome of cancer 14. Type I PCD, apoptosis, is characterized by specific morphological changes (cell shrinkage, nuclear condensation and fragmentation, and dynamic membrane blebbing) 15 and biochemical changes (chromosomal DNA cleavage into internucleosomal fragments, phosphatidylserine externalization, and intracellular substrate cleavage by specific proteolysis) 16. Type II PCD, autophagy, is a cellular homeostatic, catabolic degradation response. It begins when double-membrane vesicles form and engulf proteins, cytoplasm, protein aggregates, and organelles, which are then delivered to lysosomes, where they are degraded to serve as alternate energy sources 1718. Autophagy allows prolonged survival of tumor cells, with consequential defects in apoptosis 19. Recent evidence shows that inhibition of autophagy restores chemosensitivity and enhances tumor cell death 20. Therefore, the inhibition of autophagy by anticancer reagents has been recognized as an important component of cancer therapy 2122.


Fisetin has been examined in the context of cancer treatment and has been shown to induce apoptosis in cancer cells. However, no reports have yet examined the effects of fisetin on autophagy in a human OSCC cell lines. The present study was conducted to investigate whether fisetin can induce autophagy in OSCC cells, and to determine its underlying molecular mechanisms.


Rest at source: https://www.ncbi.nlm...les/PMC6329852/


Also tagged with one or more of these keywords: oral squamous cell carcinoma, fisetin, apoptosis, autophagy

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