Dimethyl fumarate and the oleanane triterpenoids, CDDO-imidazolide and CDDO-methyl ester, both activate the Nrf2 pathway but have opposite effects in the A/J model of lung carcinogenesis.
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 264.7 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 RAW264.7 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 12.5 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 < 0.05). 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 < 0.05). Additionally, DMF significantly increased the average number of tumors compared with the controls (P < 0.05). 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.
Department of Pharmacology.
Ciric
C
To
Department of Genetics and.
Carol S
CS
Ringelberg
Department of Pharmacology.
Darlene B
DB
Royce
Department of Pharmacology.
Charlotte R
CR
Williams
Department of Pharmacology.
Renee
R
Risingsong
Department of Pharmacology.
Michael B
MB
Sporn
Department of Pharmacology, Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA karen.t.liby@dartmouth.edu.
Karen T
KT
Liby
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000069462:Dimethyl Fumarate; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000972:Antineoplastic Agents, Phytogenic; D005650:Fumarates; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C413246:oleanane; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D000069462:Dimethyl Fumarate