Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma

Abstract

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.

Downregulation of long non‑coding RNA UCA1 enhances the radiosensitivity and inhibits migration via suppression of epithelial‑mesenchymal transition in colorectal cancer cells

“…The G2 arrest in tumor cells provides time for the repair processes to operate which are critical for ensuring cell survival after DNA damage (41). It was suggested that the combination of BI-69A11 and celecoxib impaired IR-induced DSB repair, attenuated the G2/M cell cycle and then enhanced the radiosensitivity of CRC cancer cells (42). In the present study, CCL244 cells with irradiation revealed prolonged G2/M phase arrest.…”

Three‐Arm, Biotin‐Tagged Carbazole–Dicyanovinyl–Chlorambucil Conjugate: Simultaneous Tumor Targeting, Sensing, and Photoresponsive Anticancer Drug Delivery

“…The in vitro anticancer activity was measured by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT; a yellow tetrazole) assay in HeLa cells. Different concentrations of CBL, 5 , and 6 were added to the wells and subjected to photolysis.…”

Downregulation of Ubiquitin-conjugating Enzyme UBE2D3 Promotes Telomere Maintenance and Radioresistance of Eca-109 Human Esophageal Carcinoma Cells

“…Radioresistance can be regulated by a series of pathways, including DNA damage repair 2 , telomere maintenance 3 , cell cycle progression 4 , cell apoptosis 5 , and cell proliferation 6 . Some reports have shown that the ubiquitin/proteasome system (UPS) participates in the regulation of these pathways 7 .…”