Date of Award
Open Access Thesis
Recent developments in the field of cancer genomics have shown transcription factor HIF-1α as a major player in the survival and proliferation of colorectal tumors. Hypoxia targeted drug engineering has led to significant advancements in cancer treatments as a method of directly utilizing the hypoxic regions against the tumor. Novel drug DCQ (2-benzoyl-3-phenyl 6,7-dichloroquinoxaline 1,4-dioxide) has shown promising anti-tumor results in-vitro and in-vivo. The purpose of this study was to utilize a tumor xenograft and genetic mouse model of colorectal cancer to investigate the safety, clinical effectiveness, and mechanism of action of DCQ. Methods: 10 week old Balb/c mice were injected subcutaneously with 2 million CT-26 cells and were monitored for tumor growth over 14 days before receiving treatment. Apcmin/+ mice were clinically evaluated from 8 weeks of age and began treatments at 16 weeks of age. DCQ treatment given at a 17mg/kg dose and 100μL DMSO injection as control. Injections were given bi-weekly over a four week period. Results: DCQ caused significant decrease in tumor weight (p<0.05) and final tumor area (p<0.05) in Balb/c mice at time of sacrifice than control and Apcmin/+ mice showed significantly lower clinical score after 1 week of therapy along with decreased large tumor size (p<0.05) and number (p<0.05). Histological analysis showed increased total apoptotic area (p<0.05) in tumor tissue sections and tumor specific apoptosis in colon tissue in both models. Western blot analysis of Balb/c showed a decreased nuclear expression of HIF-1α (p<0.05) and increased expression of pro-apoptotic genes dephosphorylated-Bad (p<0.001), cleaved caspase-9 (p<0.05), and Bax (p<0.05) paralleled with a decrease in anti-apoptotic Bcl-2 gene (p<0.05). Conclusions: DCQ induces tumor specific apoptosis through mechanisms involving down regulation of HIF-1α and increased intracellular apoptosis in Balb/c mice and Apcmin/+ mice. Novel drug DCQ may potentially have use as a chemotherapeutic agent to reduce the pathology of sporadic intestinal and colorectal cancers.
Sougiannis, A. T.(2015). Novel Drug 2-benzoyl-3-phenyl 6,7-dichloroquinoxaline 1,4-dioxide Induces Colon Cancer Cell Apoptosis Through HIF-1α Pathway. (Master's thesis). Retrieved from http://scholarcommons.sc.edu/etd/3649