Abstract 1805: DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT)

Abstract

Abstract The most conventional therapy for solid tumors is radiotherapy. Still there is a challenge when it comes to managing highly disseminated gastrointestinal cancers because of the toxicity issues. Earlier, low dose fractionated radiotherapy (LDFRT) was considered to be ineffective for tumor removal, rather believed to cause cancer. There are few improvements with the use of novel approach in few cases of solid malignancy. This paradigm exploits the advantage of LDFRT with the combination of chemotherapy. Because now it's known that LDFRT causes hyper-radiosensitivity (HRS). The aim of our study is to determine the efficacy of LDFRT in combination with modified regimen of docetaxel, cisplatin and 5′-fluorouracil (mDCF) and their mechanism of action in gastric cancer cells. Our data indicate that consecutive three days radiation with daily fraction of 0.15 Gy produced HRS in gastric cancer cells and potentiated the effect of chemotherapeutic drugs (mDCF). Colony survival assays showed only 10% of gastric cancer cell survival when LDFRT was combined with mDCF while ten times higher dose (1.35 Gy) of radiation alone was required to achieve the same results. RT2-PCR profiler array analysis showed marked upregulation of dual oxidase-2 (DUOX2), an enzyme of NADPH- oxidase family, without inducing the genes involved in DNA repair. This was evident from 3.5 fold increase in reactive oxygen species (ROS) in cells exposed to LDFRT and mDCF. Further, this was confirmed by increase in cancer cell survival hence radioresistance with downregulation of DUOX2 expression. In addition to this inhibition of DUOX2 activity also abrogated the efficacy of the combination therapy. Taken together these data suggest that chemopotentiation by LDFRT in gastric cancer cells may be partly due to increased ROS production by DUOX2 without inducing the DNA repair machinery. These data thus provide a rationale for further explorations of potential clinical applications of LDFRT as a chemopotentiator for advanced and metastatic gastric cancers. (* = Equally Contributed) Citation Format: Duc Nguyan, Palak R. Parekh, Elizabeth T. Chang, Navesh Sharma, France Carrier. DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1805. doi:10.1158/1538-7445.AM2015-1805