الفهرس 
Introduction.Only 14 pages are availabe for public view
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Abstract
Oral squamous cell carcinoma represents a large section of oral cancer and remains a life-threatening problem with few successful treatments available worldwide. One of the methods of efficiently eradicating cancer cells is by stimulating apoptosis. All apoptotic pathways lead to Casp3 activation. Thus, it is essential for inducing apoptosis by cancer treatments.
The PI3K/AKT/mTOR pathway is affected in several cancers, such as HNSCC, and its dysregulation promotes cancer development and progression. Buparlisib is a pan PI3K inhibitor undergoing investigation in different cancer types. It mediates its role through many mechanisms, like promoting apoptosis. The correlated side effects and treatment resistance are the restrictions obscuring its general use in cancers.
Vitamin D, with its active form calcitriol, has a wide range of functions in normal and cancer cells. In neoplastic cells, it modulates different cellular activities, such as proliferation, apoptosis, growth, angiogenesis, and differentiation. The antineoplastic effect of Vit D is also maintained by modulating the PI3K/AKT/mTOR pathway.
Despite the available data on Vit D, we need more research to comprehend its actions and effects on HNSCC. This study aimed to determine the impact of Buparlisib and Vit. D, separately, and their coadministration on the viability, AKT1, and Casp3 gene expression of the HNO-97 cell line.
The study consisted of nine subgroups examined after 48 h. The G1 group was the untreated cells, and the four single agent groups consisted of two Buparlisib doses (B1 and B2) and two Vit D doses (D1 and D2). The four combination groups were the IC50 and IC70 coadministration doses of Buparlisib with Vit D (C1, C2, C3, and C4).
The HNO-97 cell line was cultured, the IC50 and IC70 Buparlisib doses were estimated, and the two selected Vit D doses (100 and 1000 nmol) were prepared. The doses were applied to the cells according to the study groups and compared to untreated cells for 48 h.
The MTT assay was performed to evaluate the effect of different treatments on the metabolic activity of HNO-97 cells. qRT-PCR was used to analyze the treatment effects on the AKT1 and Casp3 RNA gene expressions.
The viability assay results revealed that the G1 sgroup significantly differed from all other groups except the D1 subgroup. The two Buparlisib doses differed statistically from one another. B1 group differed from D1, D2, and C4 groups, and B2 differed from the two Vit D doses only. The two Vit D doses were statistically significant from all coadministration doses with a p value of < 0.001.
Analyzing the upregulated Casp3 RNA gene expression, G1 showed statistical differences compared to B2 and the four coadministration subgroups. B1 showed a statistical difference from the four coadministration groups (p < 0.001). Similarly, B2 differed significantly from C1 (p = 0.002), C2, C3, and C4 groups (p < 0.001). Comparing D1 to D2 groups manifested a non-statistical difference. Regarding the four coadministration subgroups, the C1 group differed significantly from C3 (p = 0.001) and C4 subgroups (p = 0.001), the C2 subgroup varied from C4 (p < 0.001), and C3 altered from C1 and C4 subgroups (p < 0.001).
As for the downregulated AKT1 gene expression, G1 showed a statistically significant difference from B2, D2, and the four co-administration doses. B1 showed a statistically significant alteration from C2 (p = 0.040), C3 (p = 0.004), and C4 (p = 0.001) subgroups only, while B2 had a statistically significant alteration from the D1 subgroup (p = 0.015). A statistically significant difference was present when comparing D1 to the four co-administration doses. Meanwhile, the D2 subgroup exhibited a statistically significant difference from the C4 subgroup (p = 0.013).
We concluded from the current study that Vit D as a single agent has a slight cytotoxic effect on the HNO-97 cell line, while its coadministration with Buparlisib mediated a pronounced effect in reducing the viability of HNO-97 which was observed by promoting apoptosis and suppressing the PI3K/AKT/mTOR pathway. These findings imply that Vit D is a promising clue for obtaining low and effective Buparlisib doses with significantly enhanced effects than Buparlisib alone. Eventually, the coadministration of Buparlisib with Vit D could be a curative therapy for cancer patients and a novel solution for this fatal disease.