Am J Pharmacol | Volume 4, Issue 2 | Research Article | Open Access

Exploring the Antitumor Effects of Dasatinib Alone or in Combination with Celecoxib in HCT-116 Colorectal Carcinoma Cell Line

Nermine Moussa1 *, Sherihan Youssef1, Medhat Haroun1 and Maged W Helmy2

Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Egypt 2 Department of Pharmacology and Toxicology, Damanhur University, Damanhur, Egypt

*Correspondance to: Nermine Moussa 

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Abstract

Colorectal cancer is a heterogeneous disease driven by genetic and epigenetic changes that allow cells to overgrow and evade programmed cell death. Many of these changes map to overlapping signal transduction cascades that govern cell proliferation/invasion/metastasis. Novel approaches for better disease management aimed at co-targeting more than one of these cascades. Src and cyclooxygenase-2 are plausible targets involved in the pathogenesis of colorectal cancer. In this context, the present work was carried out to unravel the anticarcinogenic effects resulting from co-targeting Src and cyclooxygenase-2 pathways using dasatinib as a Src inhibitor, and celecoxib as a selective cyclooxygenase-2 inhibitor in HCT-116 colorectal carcinoma cell line. MTT cell proliferation assay was used to determine the GI50 of both drugs. HCT-116 cells were treated with dasatinib, celecoxib, and their combination at their GI50s along with a control group for 72 h. Then, cells were collected and pellets were stored at -80°C. After that, cells were prepared for ELISA to determine c-Src, NF-κB, TNF-Aα, p-AKT, p-STAT-3, MMP-9, cyclin D1, caspase-3, and VEGF protein levels. Expression of c-Src gene was assessed by quantitative real-time PCR. On one hand, Dasatinib, Celecoxib, and their combination reduced c-Src, NF-κB, TNF-Aα, p-AKT, STAT-3, VEGF, MMP-9, and Cyclin D1 protein levels compared with the control group. On the other hand, there was no statistically significant difference in caspase-3 protein level upon Dasatinib and Celecoxib treatments, but Dasatinib/Celecoxib combination exerted a pronounced effect on caspase-3 protein level. c-Src gene was up-regulated by 1.3, and 1.7-fold by each of Dasatinib and Celecoxib, respectively; however, the combination didn't influence c-Src gene expression level. To sum up, the combination has a beneficial role that results from the use of Celecoxib as an add-on therapy to Dasatinib. This needs to be explored in other types of cancer and in cancer patients as Celecoxib can be used as adjuvant therapy for the reduction of inflammation and proliferation in addition to apoptosis stimulation.

Keywords:

Colorectal cancer is a heterogeneous disease driven by genetic and epigenetic changes that allow cells to overgrow and evade programmed cell death. Many of these changes map to overlapping signal transduction cascades that govern cell proliferation/invasion/metastasis. Novel approaches for better disease management aimed at co-targeting more than one of these cascades. Src and cyclooxygenase-2 are plausible targets involved in the pathogenesis of colorectal cancer. In this context, the present work was carried out to unravel the anticarcinogenic effects resulting from co-targeting Src and cyclooxygenase-2 pathways using dasatinib as a Src inhibitor, and celecoxib as a selective cyclooxygenase-2 inhibitor in HCT-116 colorectal carcinoma cell line. MTT cell proliferation assay was used to determine the GI50 of both drugs. HCT-116 cells were treated with dasatinib, celecoxib, and their combination at their GI50s along with a control group for 72 h. Then, cells were collected and pellets were stored at -80°C. After that, cells were prepared for ELISA to determine c-Src, NF-κB, TNF-Aα, p-AKT, p-STAT-3, MMP-9, cyclin D1, caspase-3, and VEGF protein levels. Expression of c-Src gene was assessed by quantitative real-time PCR. On one hand, Dasatinib, Celecoxib, and their combination reduced c-Src, NF-κB, TNF-Aα, p-AKT, STAT-3, VEGF, MMP-9, and Cyclin D1 protein levels compared with the control group. On the other hand, there was no statistically significant difference in caspase-3 protein level upon Dasatinib and Celecoxib treatments, but Dasatinib/Celecoxib combination exerted a pronounced effect on caspase-3 protein level. c-Src gene was up-regulated by 1.3, and 1.7-fold by each of Dasatinib and Celecoxib, respectively; however, the combination didn&39;t influence c-Src gene expression level. To sum up, the combination has a beneficial role that results from the use of Celecoxib as an add-on therapy to Dasatinib. This needs to be explored in other types of cancer and in cancer patients as Celecoxib can be used as adjuvant therapy for the reduction of inflammation and proliferation in addition to apoptosis stimulation

Citation:

Moussa N, Youssef S, Haroun M, Helmy MW. Exploring the Antitumor Effects of Dasatinib Alone or in Combination with Celecoxib in HCT-116 Colorectal Carcinoma Cell Line. Am J Pharmacol. 2021; 4(2): 1034..

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