New thiophene derivative augments the antitumor activity of γ-irradiation against colorectal cancer in mice via anti-inflammatory and pro-apoptotic pathways.

BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer worldwide and the second cause of cancer-related deaths. It usually starts as an inflammation that progresses to adenocarcinoma. The goal of the present study was to investigate the antitumor efficacy of a new thiophene derivative against CRC in mice and explore the possible associated molecular pathways. The potential of this thiophene derivative to sensitize the CRC tumor tissue to a low dose of gamma irradiation was also investigated. METHODS: Adult male mice were divided into seven groups; control, group treated with dimethylhydrazine (DMH) for the induction of CRC. The DMH-group was further divided into six groups and treated with either cisplatin, thiophene derivative, γ-irradiation, cisplatin + γ-irradiation, thiophene derivative + γ-irradiation, or left untreated. RESULTS: DMH induced CRC as evidenced by the macroscopic examination of colon tissues and histopathology, and elevated the activities of cyclooxygenase2 (COX2) and nitric oxide synthase (iNOS). DMH also elevated kirsten rat sarcoma (KRAS) and downregulated the peroxisome proliferator activated receptor (PPARγ) as shown by RT-PCR and Western blotting. DMH exerted anti-apoptotic activity by reducing the expression of phosphorylated p53 and cleaved caspase3 at the gene and protein levels. The flow cytometry analysis showed that DMH elevated the necrosis and reduced the apoptosis compared to the other groups. The colon tissue from DMH-treated mice showed hyperplasia, aberrant crypt foci, loss of cell polarity, typical CRC of grade 4 with lymphocytes and macrophages infiltrating mucosa, muscularis mucosa, and submucosa score 3. Treatment with thiophene derivative or γ-irradiation ameliorated most of these deleterious effects of DMH. The concomitant action of thiophene derivative + γ-irradiation was typified by the better amelioration of tumor incidence and multiplicity, iNOS, PPARγ, p53, caspase 3, and histopathology of colon. CONCLUSION: Taken together, the new thiophene derivative is a promising therapeutic candidate for treatment of colorectal cancer in mice. It also sensitizes the CRC tumor to the ionizing radiation through anti-inflammatory and pro-apoptotic pathways.