Inhibition of colon carcinogenesis by post-initiation induction of NQO1 in Sprague-Dawley rats.
Inducers of phase II detoxifying enzymes have been studied as chemopreventive agents for a variety of cancers. Phase II detoxifying enzymes may play a significant role in preventing carcinogen-induced colon cancer at the initiation and post-initiation stage, but the contribution of NAD(P) H:quinone oxidoreductase 1 (NQO1) to this effect remains unclear. Using the carcinogen-induced colon cancer Sprague-Dawley rat model, we previously showed that oltipraz selectively induces NQO1 in the colons of these rats without inducing other phase II detoxifying enzymes. We demonstrated that selective induction of NQO1 in the rat colon prior to treatment with a carcinogen significantly inhibited the formation of aberrant crypt foci (ACF). Using the same rat model, we found that rats fed oltipraz containing diet following treatment with the colon carcinogen, azoxymethane (AOM), had 60% fewer ACF after 12 weeks compared with rats fed a control diet. In addition, rats fed oltipraz containing diet after AOM treatment developed 40% fewer colon adenomas and fewer colon tumors than rats fed a control diet. There was also a 60% increase in the percentage of apoptotic cells in ACF from oltipraz fed rats compared with ACF from control fed rats. Together, these results suggest that NQO1 can contribute to inhibition of colon carcinogenesis at the post-initiation stage. A possible mechanism for this effect may be that induction of NQO1 increases apoptosis in carcinogen initiated colonic epithelial cells that prevents these cells from progressing to a neoplastic state. Thus, NQO1 may be an important target for chemoprevention of colon cancer.
Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada. begleit@cc.umanitoba.ca
Asher
A
Begleiter
Kosala
K
Sivananthan
Georgia M
GM
Lefas
Andrew W
AW
Maksymiuk
Ranjana P
RP
Bird
D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D009374:Neoplasms, Experimental; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D001397:Azoxymethane