Abstract LB-265: Comparison of oleanane triterpenoids and dimethyl fumarate in lung cancer

Abstract

Abstract Lung cancer accounts for the highest number of cancer-related deaths in the United States, highlighting the need for better therapies. Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in mouse macrophages (Raw 264.7) and in VC1 lung cancer cells. Although both triterpenoids and DMF activated Nrf2, CDDO-Im and CDDO-Me were more potent than DMF. Specifically, 25-50 nM CDDO-Im or CDDO-Me increased NQO1 and HO-1 expression 100-fold. Conversely, 10 μM of DMF was necessary to elicit the same effect. Additionally, 100 nM of CDDO-Im significantly (p<0.05) reduced ROS production induced by tert-butyl hydroperoxide by 69%, while 10 μM of DMF reduced ROS production by 44%. Moreover, nitric oxide production was significantly decreased by triterpenoids at nanomolar concentrations while DMF had a similar effect at micromolar concentrations (p<0.05). Using microarray analysis, we examined whether these Nrf2 activators target the same genes. Only 52 of 99 Nrf2 genes were targeted by all three compounds, and each drug targeted a unique subset of Nrf2 genes. Notably, CDDO-Im, CDDO-Me and DMF induced HO-1 expression by 9.1, 5.3 and 1.6 fold respectively. We then utilized Nrf2 knockout fibroblasts to confirm that induction of HO-1 expression was regulated via both Nrf2-dependent and Nrf2-independent pathways. To examine the effect of these Nrf2 activators in vivo, A/J mice were injected with vinyl carbamate to induce lung cancer. Beginning one week after initiation, mice were fed drugs in diet for 15 weeks. CDDO-Me was the most effective drug in this model; it reduced the average number and size of tumors by 32% (2.2 ± 0.3) and 76% (0.09 ± 0.01), respectively, compared to controls (3.2 ± 0.2 and 0.4 ± 0.04; p<0.05). Average tumor burden was also reduced by 83% (0.2 ± 0.03), compared to the controls (1.2 ± 0.1; p<0.05). Additionally, the percentage of high-grade tumors significantly decreased from 52% in the controls to 31% in the CDDO-Me group (p<0.05). Though less potent, CDDO-Im had similar effects as CDDO-Me. In contrast, when mice were fed DMF in diet, the average number of tumors increased by 29% (4.1 ± 0.4) compared to controls (3.2± 0.2; p<0.05). The percentage of high-grade tumors in mice fed DMF diet also increased to 63% vs. 52% in the controls (p<0.05). These data indicate that DMF increased the severity of lung carcinogenesis in these mice. Collectively, our study suggests that although CDDO-Im, CDDO-Me and DMF all activate Nrf2, they target distinct genes, resulting in different effects for the prevention of lung cancer. Citation Format: Ciric To, Darlene B. Royce, Charlotte R. Williams, Renee Risingsong, Michael B. Sporn, Karen T. Liby. Comparison of oleanane triterpenoids and dimethyl fumarate in lung cancer. [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 LB-265. doi:10.1158/1538-7445.AM2015-LB-265