Showing papers by "Michael B. Sporn published in 2015"
TL;DR: Results suggest that although CDDO-Im,CDDO-Me and DMF all activate the Nrf2 pathway, they target distinct genes and signaling pathways, resulting in opposite effects for the prevention of experimental lung cancer.
Abstract: Lung cancer accounts for the highest number of cancer-related deaths in the USA, highlighting the need for better prevention and therapy Activation of the Nrf2 pathway detoxifies harmful insults and reduces oxidative stress, thus preventing carcinogenesis in various preclinical models However, constitutive activation of the Nrf2 pathway has been detected in numerous cancers, which confers a survival advantage to tumor cells and a poor prognosis In our study, we compared the effects of two clinically relevant classes of Nrf2 activators, dimethyl fumarate (DMF) and the synthetic oleanane triterpenoids, CDDO-imidazolide (CDDO-Im) and CDDO-methyl ester (CDDO-Me) in RAW 2647 mouse macrophage-like cells, in VC1 lung cancer cells and in the A/J model of lung cancer Although the triterpenoids and DMF both activated the Nrf2 pathway, CDDO-Im and CDDO-Me were markedly more potent than DMF All of these drugs reduced the production of reactive oxygen species and inhibited nitric oxide production in RAW2647 cells, but the triterpenoids were 100 times more potent than DMF in these assays Microarray analysis revealed that only 52 of 99 Nrf2-target genes were induced by all three compounds, and each drug regulated a unique subset of Nrf2 genes These drugs also altered the expression of other genes important in lung cancer independent of Nrf2 Although all three compounds enhanced the phosphorylation of CREB, only DMF increased the phosphorylation of Akt CDDO-Me, at either 125 or 50mg/kg of diet, was the most effective drug in our lung cancer mouse model Specifically, CDDO-Me significantly reduced the average tumor number, size and burden compared with the control group (P < 005) Additionally, 52% of the tumors in the control group were high-grade tumors compared with only 14% in the CDDO-Me group Though less potent, CDDO-Im had similar activity as CDDO-Me In contrast, 61-63% of the tumors in the DMF groups (400-1200mg/kg diet) were high-grade tumors compared with 52% for the controls (P < 005) Additionally, DMF significantly increased the average number of tumors compared with the controls (P < 005) Thus, in contrast to the triterpenoids, which effectively reduced pathogenesis in A/J mice, DMF enhanced the severity of lung carcinogenesis in these mice Collectively, these results suggest that although CDDO-Im, CDDO-Me and DMF all activate the Nrf2 pathway, they target distinct genes and signaling pathways, resulting in opposite effects for the prevention of experimental lung cancer
60 citations
TL;DR: The findings indicate that Nrf2 exhibits a retinal neuroprotective function in I/R and suggest that pharmacologic activation of NRF2 could be a therapeutic strategy.
Abstract: Retinal ischemia plays a critical role in multiple vision-threatening diseases and leads to death of retinal neurons, particularly ganglion cells Oxidative stress plays an important role in this ganglion cell loss Nrf2 (NF-E2-related factor 2) is a major regulator of the antioxidant response, and its role in the retina is increasingly appreciated We investigated the potential retinal neuroprotective function of Nrf2 after ischemia-reperfusion (I-R) injury In an experimental model of retinal I/R, Nrf2 knockout mice exhibited much greater loss of neuronal cells in the ganglion cell layer than wild-type mice Primary retinal ganglion cells (RGCs) isolated from Nrf2 knockout mice exhibited decreased cell viability compared to wild-type RGCs, demonstrating the cell-intrinsic protective role of Nrf2 The retinal neuronal cell line 661W exhibited reduced cell viability following siRNA-mediated knockdown of Nrf2 under conditions of oxidative stress, and this was associated with exacerbation of increase in reactive oxygen species (ROS) The synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), a potent Nrf2 activator, inhibited ROS increase in cultured 661W under oxidative stress conditions and increased neuronal cell survival after I/R injury in wild-type, but not Nrf2, knockout mice Our findings indicate that Nrf2 exhibits a retinal neuroprotective function in I-R and suggest that pharmacologic activation of Nrf2 could be a therapeutic strategy
54 citations
TL;DR: Drugs tested for prevention in a highly relevant mouse lung cancer model were as effective as CDDO-Im for reducing the size and the severity of the lung tumors and pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO -Im.
25 citations
Patent•
26 Aug 2015TL;DR: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana- 1,9(11 ) -dien-28-oyl) imidazole and pharmaceutical compositions containing the same are provided in this article.
Abstract: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana- 1,9(11 ) -dien-28-oyl) imidazole and pharmaceutical compositions containing the same are provided. The present invention is a tnterpenoid compound of Formula I, or a hydrate, isomer, prodrug or pharmaceutically acceptabl salt thereof: wherein one or more of R, R or R is independently a substituted or unsubstituted aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, and the remaining R groups are hydrogen. The pyridyl analogs of CDDO-lm 1 have been developed, which are more stable in human plasma and achieve a higher concentration in target tissues such as liver, pancreas, kidney and lungs.
3 citations