الفهرس 
ENGLISH ABSTRACTOnly 14 pages are availabe for public view
 |  | from | 100 |  |  |
| | | from | 100 | | |
Abstract
Oral squamous cell carcinoma stands as one of the most difficult tumors to manage because of its high ability for local invasion and metastasis. In spite of the improvements in the therapeutic approaches (surgery followed by combined radio-chemotherapy), the prognosis is still unsatisfactory. The survival rates have not improved through the past 20 years, with high mortality records.
Cancer immunotherapy, also named as immuno-oncology, is a treatment method for cancer which uses the capability of the body’s own immune system to detect, control, and eliminate cancer cells. The innate immunity is involved in both protumor and antitumor processes.
Toll-like receptors (TLRs) are pattern recognition sensors that mainly expressed in the innate immune cells, fibroblasts, and epithelial cells. Marked over expression of TLRs has been detected in many tumors, indicating that they could be involved in the pathophysiology of cancer.
Various researches have proved that dysregulated toll-like receptor 4 (TLR4) signaling enhances the proliferation, migration and metastasis of cancer cells. TAK-242 (resatorvid) is a small molecule inhibitor of TLR4 which specifically and selectively links to the intracellular portion of the receptor and inhibits all TLR4 interplays with its downstream signaling molecules. In consequence, the activation of nuclear factor-kappa (NF-κB), and the correlated cytokines is prevented. Furthermore, many researches have shown that TAK-242 has no effect on TLR1, 2, 3, 5, 6, 7, 9, nor does it interfere with TLR4 dimerization.
The objectives of the current study were to verify the expression of TLR4 in oral squamous cell carcinoma cell line (SCC4) using immunohistochemistry and to assess the anticarcinogenic properties of its antagonist; TAK-242.
The anti-cancer effect of the TAK-242 against SCC4 cell line was assessed through cytotoxic assay to calculate and verify the IC50, detection of apoptosis, proliferation status, and cell cycle analysis using flow cytometer assay, and determination of the anti-migratory effect using wound healing assay.
The immunocytochemical analysis of the present study proved that SCC4 cells positively expressed TLR4. Evident cytoplasmic reaction was detected in all cells with lacking of the reaction in the nuclei. The cytolethal action of TAK-242 was in a dose-depended pattern, by increasing the concentration of the inhibitor, the cell viability continued to decrease significantly.
The results of Annexin V/PI apoptosis detection assay revealed a significant increase in the early and late apoptosis in comparison with the untreated cells. In addition, TAK-242 showed marked antiproliferative properties by arresting the cell division in G2/M phase.
The Ki-67 proliferation assay proved that treatment with the TLR4 blocker, TAK-242, significantly lowered the percentage of the proliferating cells in comparison with the control group. The results of the migration assay revealed that the inhibition of TLR4 using TAK-242 showed high potency in retarding the migratory capacity of SCC4 cells. The width of the wound gap was noticeably increased after 24 hours of treatment. While after 48 hours the width of the cell-free zone was immeasurable. The cytotoxic effect of TAK-242 caused cell death, therefore almost no cells have remained for measurement.