A formula constituted by arsenic trioxide and dimercaprol enhances sensitivity of pancreatic cancer xenografts to radiotherapy

Abstract

Objective To investigate the efficacy of the formula constituted by arsenic trioxide (ATO) and dimercaprol (BAL), BAL-ATO, as a radiosensitizer against pancreatic cancer xenografts. Methods Four treatment arms, including the control, radiotherapy (RT), BAL-ATO and RT + BAL-ATO, were examined using mouse models bearing SW 1990 human pancreatic cancer xenografts. Besides survival and tumor volume analysis, living imaging for cell apoptosis in tumor samples, confocal laser microscope observation for hypoxia, western blot and immunohistochemistry (IHC) assays were employed to detect the mechanism of BAL-ATO in radiotherapy. Results The median survival of the combination (RT + BAL-ATO) group (64.5 days) was significantly longer than those of the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( P < 0.001 ). Compared to the control group, RT + BAL-ATO inhibited the growth of tumors in mice by 73%, which was much higher than the rate of inhibition of RT alone (59%). The further analysis results also showed an improved microenvironment with regard to hypoxia in tumors treated by BAL-ATO alone or RT + BAL-ATO; besides, the suppression of signals, such as CD24, CD44, ALDH1A1, Gli-1 and Nestin, those associating with pancreatic cancer stem cells (PCSCs), were detected in the tumor samples treated by BAL-ATO alone or RT combing with BAL-ATO. Conclusion The data suggested that BAL-ATO, a formula constituted by ATO and BAL, could function as a sensitizer to radiotherapy for pancreatic cancer xenografts, and the mechanism might be attributed to hypoxia reduction and inhibition to signal pathways associated with PCSCs.