Abstract B20: Arsenic trioxide, ascorbic acid, and disulfiram (AAA) arrests pancreatic cancer development in a transgenic mouse model with disrupted p16-activated Kras.

Abstract

Previously, we found that four human pancreatic cancer cell lines underwent robust cell death associated with ATP decline and ROS accumulation when treated with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (AAA). Early apoptosis was shifted to aponecrosis, and dependent on VDAC, since shRNA directed against VDAC-1 and preliminary data for VDAC-3 abrogated the ROS accumulation and blocked cell death. In addition, preliminary studies show that celecoxib enhances AAA-induced pancreatic cancer cell death and is dependent on Cox-2. In this study, assessment of AAA was performed in Pdx1-Cre transgenic mice with a conditional p16 knockout (p16flox/flox), and oncogenic KrasG12D. The KrasG12D, p16flox/flox; LSL-KrasG12D; Pdx1-Cre mice develop the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma (PDA), and frequent metastases. Eight-week-old mice were treated for 8 weeks, 3 times/week with AAA, sacrificed, and the development of pancreatic cancer assessed. Little or no toxicity of the mice to the AAA treatment was observed. The development of frank pancreatic tumors was eliminated in AAA-treated mice from 31% in controls. The mean number of PanIn 3 lesions/mouse declined from 14.1 in controls to 1.58 in AAA-treated mice (p=0.008). The mean number of PanIn2 lesions declined from 5.18 in controls to 1.67 in AAA treated mice (p=0.06). The mean number of PanIn1 lesions in control mice were 14.2 and in AAA-treated mice were 16.0, p=0.51 indicating no difference in PanIn1 occurrence. Preliminary results from immunohistochemical staining of the PanIn lesions for VDAC indicated that PanIN 1 lesions have low and PanIN 2 and 3 lesions have high VDAC expression. This result parallels the in vitro human cell line data showing VDAC expression is critical to AAA sensitivity, and suggests a similar mechanism of action in vivo as in vitro. Although collection of data is ongoing, this is the first treatment that has been shown to arrest PanIn development and tumor development in this mouse model for pancreatic cancer. The preliminary data suggests that AAA either arrests the development of prepancreatic lesions after the PanIN 1 stage, or that the PanIN2 and PanIn3 lesions are killed after exposure to AAA in a VDAC-dependent manner. Citation Format: Richard D. Dinnen, Wanglong Qiu, Yuehua Mao, Gloria Su, Robert Fine. Arsenic trioxide, ascorbic acid, and disulfiram (AAA) arrests pancreatic cancer development in a transgenic mouse model with disrupted p16-activated Kras. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B20.