Abstract
PAC (3,5-Bis (4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone), a novel bioactive curcumin analog, has been reported to have anticancer properties against various tumors. However, the anti-cancer effects of PAC on oral cavity squamous cell carcinoma were not studied yet. Our aim is to investigate the anti-oral cancer properties of PAC in vitro, and determine the molecular mechanisms underlying these effects. Viability assays including MTT and LDH were conducted to measure cell proliferation. Flow cytometry-based cytotoxicity assay was performed to detect autophagic cell death and oxidative stress markers. Western blotting was used for measuring protein expression/activation in apoptotic, autophagic and pro-carcinogenic cellular signaling pathways. We demonstrated that PAC preferentially and, in a dose, -dependent way kills oral cancer cells, but was not toxic to normal human gingival cells. PAC destabilizes cell-cycle distributions, inhibits the expression of oncogenes (cyclin D1) and that of cyclin-dependent kinase inhibitor (p21WAF1) is upregulated, increases the expression of p53 gene, and inhibits epithelial-mesenchymal transition markers in oral cancer cells. The PAC effect involve various signaling pathways including NF-κB, MAPK, Wnt, caspase-3/9 and PARP1. Finally, PAC demonstrated ability to induce autophagy, decrease production of reactive oxygen species, increase intracellular glutathione (GSH) activity, and reduce mitochondrial membrane potential in oral cancer cells. In conclusion, PAC inhibits the proliferation and increases the apoptosis and autophagy and oxidative stress of oral cancer cells. These effects involve ERK1/2, p38/JNK, NF-κB and Wnt cellular signaling pathways. Overall, our study suggests the potential use of PAC to treat oral cancer.
Highlights
PAC selectively inhibits the growth of oral cancer cells, and increases apoptosis
We demonstrated a significant effect of PAC reducing the capacity of oral cancer cells to form colony but not in gingival epithelial cells (GEC) (Fig. 1E)
We demonstrated that anti-proliferative effect of PAC on oral cancer cells goes through a cell cycle modification
Summary
Because the patient may not notice it in its first stages, as it can frequently thrive without generating pain or symptoms, and generally, it produces primary tumors This means that patients, who survive a first encounter with the disease, have up to 20 times higher risk of developing a second cancer[3]. Despite its survival benefits as an anticancer drug, it has side effects, especially the chemoresistance that is limiting patients in clinical effectiveness[7] This knowledge has inspired the use of herbal medicinal products as complementary and/or alternative therapies to a direct remedy, the recognition of plant products as effective and inexpensive sources of novel synthetic chemotherapeutic compounds is increasing. This research is aiming at studying the inhibitory effects of the curcumin analog PAC on oral cell proliferation and apoptosis, as well as investigating the signaling pathways involved in the interactions of PAC with oral cancer cells
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