title: 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.
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Pal
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors.forename: Kaushik Kumar
authors.initials: KK
authors.lastname: Dey
authors.affiliation: Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Chaurasia
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Parida
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors.forename: Subhayan
authors.initials: S
authors.lastname: Das
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors.forename: Y
authors.initials: Y
authors.lastname: Rajesh
authors.affiliation: Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Saroj Gupta Cancer Center and Research Institute, Thakurpukur, Kolkata, West Bengal, India.
authors.forename: Tamohan
authors.initials: T
authors.lastname: Chowdhury
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India. mahitosh@smst.iikgp.ernet.in.
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001562:Benzimidazoles / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000068579:Celecoxib / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D015363:Quinolones / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones; D011838:Radiation-Sensitizing Agents; D000068579:Celecoxib
keywords: BI-69A11; Celecoxib; Colon carcinoma; DNA damage repair; Radiosensitization