Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma
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Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti-apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy.
KeywordsRadiosensitization BI-69A11 Celecoxib DNA damage repair Colon carcinoma
We thank DBT for the grant support. We thank Dr. PB Fisher and Dr. Maurizio Pellecchia for providing us the key compound BI-69A11 for research purpose and for their kind help. We also thank Mr. Priyanshu for his kind help.
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Conflicts of interest
- 50.Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, et al. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-Akt signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res. 2006;12:4119–26.CrossRefPubMedGoogle Scholar
- 77.Kazi A, Sun J, Doi K, Sung SS, Takahashi Y, Yin H, et al. The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and Mcl-1 protein-protein interactions with BAX, BAK, BAD, or BIM and induces apoptosis in a BAX- and BIM-dependent manner. J Biol Chem. 2011;286:9382–92.CrossRefPubMedGoogle Scholar