الفهرس 
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Abstract
Summary
Squamous cell carcinoma (SCC) is the most common malignant neoplasm affecting the head and neck region, and the incidence of SCC has been steadily increasing over the past couple of decades in spite of current advances in the diagnosis and treatment.
The PI3K/Akt signaling pathway is of major significance in head and neck squamous cell carcinoma (HNSCC), as it is the most frequently mutated pathway. In general, this signaling pathway promotes cell survival, development, growth and differentiation.
Recently, the dysregulation of this pathway has been studied at the genomic and proteomic levels, as it has a key role in the pathogenesis of HNSCC and is a prospective therapeutic target. In addition, activation of the PI3K/Akt pathway is known to be implicated in acquired resistance to chemotherapeutic agents.
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents administrated alone or in combination with other agents. Moreover, DOX has been used in the treatment of various types of cancer including breast, uterus, ovary, esophagus and oral cancer. In spite of DOX being a potent anticancer agent, it was shown to have several side effects such as toxicity and acquired drug resistance.
Recently, the term repurposing or re-profiling has been introduced. It is the identification of new indications to already existing drugs. One form of drug repurposing is the application of a well-known non cancer drug and using them in the treatment of cancer. These repurposed agents can be administrated on their own or in the combination a chemotherapeutic agent to potentiate their effect.
Thioridazine (TZ) is a well-known repurposed drug that was originally used in the treatment of patients with schizophrenia. According to previous researches, TZ could be a promising therapeutic target in different types of cancer.
TZ is documented to act through dopamine receptors. It has been shown to induce apoptosis, anti-angiogenic, anti-metastatic effects on tumor cells. Moreover, plays a key role in the regulation of PI3/Akt pathway and mTOR signaling which is involved in TZ induced apoptosis.
This study aimed to evaluate the effect of TZ and DOX separately and in combination, with different concentrations and durations on Hep2 cell line, study the Akt gene expression using qRT-PCR, and immunocytochemistry. Finally, evaluate the efficacy of both drugs on the inhibition of cell migration in Hep2 cell line.
The study included twenty groups including control groups of HEp 2 cell without treatment for 24 and 48 hrs. The cell viability for all groups was measured after 24 and 48 hours of treatment with different doses of the drugs selected according to previous researches using MTT assay. The Akt expression was evaluated by qRT-PCR and immunocytochemistry after 24 and 48 hours of treatment with different doses of the drugs. Finally, Cell migration was evaluated after 24 hours of treatment with different doses of the drugs.
The results of this work showed that the lowest mean of cell viability was obtained with combination of drugs at high dose whether after 24 or 48 hours. There was no statistically significant difference between 5 and 10 µg/ml of combination doses.
On the other hand, qRT-CR, ICC and cell migration assay results in this study supported each other where they showed that the control group had the highest mean of Akt gene expression, Akt protein expression and cell migration count compared to other groups, followed by DOX treated groups. The combination group VI (high dose) showed the lowest mean compared to other groups.
According to the previously mentioned results, it was concluded that in spite of the fact that DOX markedly reduced the viability of cancer cells, it did not inhibit efficiently cell migration as TZ and drug combination. On the other hand, the combination group was able to overcome DOX’s drug limitations by inhibiting PI3K/Akt pathway, inhibiting cell migration via TZ’s anticancer effects. Consequently, the combination group enhanced DOX’s cytotoxic effects in addition to the anticancer effects of TZ (acting synergistically), leading to the best outcome compared to other groups in eradicating cancer cells.