الفهرس 
Introduction.Only 14 pages are availabe for public view
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Abstract
Oral squamous cell carcinoma represents 80%–90% of all malignancies in the oral cavity, most commonly in the tongue involving approximately 25% of all cases. About 50% of afflicted cases of oral squamous cell carcinoma (OSCC) survive. Although there are advances in traditional OSCC treatments including surgery, radiotherapy and chemotherapy, these advances failed to improve survival rates and have been linked to serious side effects.
Recently there is a strong tendency to shift from the conventional treat- ment options for cancer to new treatment modalities. The use of natural extracts for cancer treatment is one of the alternative treatment options and among these extracts is thymol.
New pharmaceutical product development and discovery are the main areas of attention for nanotechnology. The significance of using nan- otechnology has received special attention in the fields of nanomedicine and nanopharmaceuticals. Scientists created novel pharmaceutical med- ications aiming at increasing their therapeutic efficacy and minimizing their drawbacks.
One of the most powerful cytotoxic drugs used as a chemotherapeutic agent for many forms of cancer is Doxorubicin (DOX), an antibiotic from the anthracycline group. Despite being introduced to clinical treatment about 45 years ago, DOX is regarded as an essential anticancer medica- tion and has complicated pharmacodynamic features that maintain it as an important research topic.
One effective way to reduce Doxorubicin-induced toxicity is to alter the way the medication is administered, along with lowering the total cumu- lative dose. The medicine can be loaded into nanocarriers to improve its therapeutic effect.
It is crucial to develop an alternative strategy that could provide a so- lution to the drawbacks of with single-drug chemotherapy in order to increase the therapeutic potential of cancer chemotherapy. For this rea- son, combination treatments have received a lot of attention in order to improve long-term prognosis and reduce side effects related to high doses of single medication treatment. Compared to single-drug therapy, com- bination therapy can modulate various signaling pathways, maximizing the therapeutic effect by minimizing toxicities and it can also overcome the drug resistance processes associated with cancer treatment.
The aim of our study was to assess the cytotoxic effect of nanoformulated thymol, nanoformulated DOX and their combination then investigating the possible synergistic effect on oral squamous cell carcinoma cell line. In our study we used three doses of each drug (half IC50, IC50 and double IC50) and applied them on squamous cell carcinoma cell line at three-time intervals (12, 24 and 48 hours).
After 12, 24 and 48 hours, the combined drug formula had the highest cytotoxicity and the lowest viability percentage with the double IC50 concentration, while the nano-thymol had the lowest cytotoxicity and the highest viability with the half IC50 concentration.
Generally, nano-thymol had the least cytotoxic effect at three-time in- tervals with the three concentrations, while the combined drugs had the highest cytotoxic effect at three-time intervals with the three concentra- tions, yet there was no statistically significant difference on comparing the combined drug formula with the nanoformulated DOX at 48 hours while using the double IC50 dose.
On comparing the cytotoxic effect of nanoformulated DOX and nanofor- mulated thymol, we found that nanoformulated DOX had higher cyto- toxic effect when using half IC50 and double IC50 at three-time intervals, however , there was no statistically significant difference on comparing between them when using IC50 at 12 and 24 hours.
In our study, we also measured CASP-3 as proapoptotic tumor suppres- sor gene and C-MYC as proliferative oncogene in untreated and treated HNO-97 cells at three-time intervals after treatment with a panel of three concentrations (half IC50, IC50 and double IC50) with each drug individually and with the two drugs in combination.
Our results revealed that, the lowest fold change of CASP-3 gene expres- sion was associated with nanoformulated thymol with half IC50 at 12 hours, while the highest fold change of gene expression was associated with combined formula with double IC50 at 48 hours.
Regarding C-MYC gene expression, the combined drug formula had the lowest fold change with double IC50 at 48 hours, while the highest fold change of C-MYC gene expression was associated with nanoformulated- thymol with half IC50 at 12 hours.
For assessment of apoptosis, we calculated the nuclear area in hema- toxylin & eosin stain of oral squamous cell carcinoma cells treated with the IC50 of each of the three tested drugs at three-time intervals (12, 24 and 48 hours). According to our results, the largest nuclear diameter
was found upon treatment with the IC50 of the combined drugs formula at 12, 24 and 48 hours respectively, while the smallest nuclear diameter was found upon treatment with IC50 of nano-thymol formula at 12, 24 and 48 hours respectively.