Research Accomplishment Reports 2008

Dietary Antioxidants, NF-kB, and Carcinogenesis

H.P. Glauert
Department of Human Environmental Sciences

 

Non-Technical Summary

Certain antioxidants have been shown to prevent cancer is some studies, but the mechanism by which they do so is unclear. In this project we propose to study if dietary antioxidants can inhibit the action of a transcription factor known as nuclear factor-kB (NF-kB), and if the action of NF-kB is necessary for cancer to develop.

Project Description

AThe original objectives of the project were 1) to determine if antioxidant-induced changes in hepatic cell proliferation, apoptosis, and cellular oxidative stress in mice administered PCBs, phenobarbital, or peroxisome proliferators are mediated by NF-kB, using a knockout model in which mice are deficient in the p50 subunit of NF-kB; and 2) to determine if dietary antioxidants will inhibit lung NF-kB activation and cell proliferation, both in cultured lung cells exposed to cigarette smoke condensate and in the lungs of mice exposed to whole cigarette smoke by inhalation. In studies published in the last year we examined the effect of dietary antioxidants on the promoting activities of PCBs and if the transcription factor NF-kB is necessary for the effects of environmental agents on cell proliferation and tumor promotion. In the first antioxidant study, we examined the effect of dietary Se on the tumor promoting activities of two PCBs congeners, PCB-77 and PCB-153. We found that Se did not inhibit the number of placental glutathione S-transferase-positive foci induced during promotion by PCBs, but that the size of the lesions may be inhibited. The effects of Se on altered hepatic foci do not correlate with its effects on glutathione peroxidase and thioredoxin reductase. We next examined the effects of several antioxidant phytochemicals on the tumor promoting activity of PCB-77. We found that none of the antioxidant phytochemicals produced a clear decrease in the promoting activity of PCB-77. We then examined if inhibition of NF-kB by vitamin E is necessary for effects of vitamin E on ciprofibrate-induced cell proliferation and the inhibition of apoptosis by ciprofibrate. We found that the effects of vitamin E on cell growth parameters do not appear to be solely through decreased NF-kB activation, suggesting that vitamin E is acting by other molecular mechanisms. We examined the hypothesis that the effects of phenobarbital on cell proliferation and apoptosis are dependent on NF-kB, using a mouse model that is deficient in the p50 subunit of NF-kB. We found that the p50 subunit of NF-kB is not required for the alteration of hepatocyte proliferation or apoptosis by phenobarbital up to 34 days after its administration. However, a different response was seen in a study that examined the effect of deleting the p50 subunit of NF-kB on the hepatic tumor promoting activity of PCB-153 in mice. These data indicated that the absence of the NF-κB p50 subunit inhibits the promoting activity of PCB-153 and alters the proliferative and apoptotic changes in mouse liver in the response to PCBs. Overall, we have found over the project period that NF-kB is necessary for changes in cell proliferation, apoptosis, and tumor promotion induced by peroxisome proliferators and PCBs but not for phenobarbital. However, vitamin E induced changes in cell proliferation and apoptosis do not appear to be mediated by NF-kB; furthermore, dietary antioxidants do not inhibit the promoting activity of PCBs. The lung studies are not published at present; however, we have observed that cigarette smoke did not activate NF-kB.

Impact

The studies over the 5-year project period show that dietary antioxidants (selenium, vitamin E, antioxidant phytochemicals) do not inhibit the hepatic tumor promoting activity of PCBs; therefore increasing dietary antioxidant consumption may not be a good strategy for preventing liver cancer in individuals exposed to PCBs. However, inhibition of NF-kB activation using a knockout model inhibited the promoting activities of both peroxisome proliferators and PCBs. Therefore the inhibition of NF-kB activation in individuals exposed to PCBs may be a future chemoprevention strategy.

Publications

Tharappel, J.C., B.T. Spear, and H.P. Glauert. Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kB. Toxicol. Appl. Pharmacol. 226:338-344, 2008.

Stemm, D.N., J.C. Tharappel, H.J. Lehmler, C. Srinivasan, J.S. Morris, V.L. Spate, L.W. Robertson, B.T. Spear, and H.P. Glauert. Effect of dietary selenium on the promotion of hepatocarcinogenesis by 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl. Exp. Biol. Med. 233:366-376, 2008.

Calfee-Mason, K.G., E.Y. Lee, B.T. Spear, and H.P. Glauert. Role of the p50 subunit of NF-kB in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate. Food Chem. Toxicol. 46:2062-2073, 2008.

Glauert, H.P., J.C. Tharappel, S. Banerjee, L.S. Chan, I. Kania-Korwel, H.J. Lehmler, E.Y. Lee, L.W. Robertson, and B.T. Spear. Inhibition of the promotion of hepatocarcinogenesis by 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) by the deletion of the p50 subunit of NF-kB in mice. Toxicol. Appl. Pharmacol. 232:302-308, 2008.

Tharappel, J.C., H.J. Lehmler, C. Srinivasan, L.W. Robertson, B.T. Spear, and H.P. Glauert. Effect of antioxidant phytochemicals on the hepatic tumor promoting activity of 3,3',4,4'-tetrachlorobiphenyl (PCB-77). Food Chem. Toxicol. 46:3467-74, 2008.