Inhibition of vinyl carbamate-induced pulmonary adenocarcinoma by indole-3-carbinol and myo-inositol in A/J mice.
In previous studies, we reported that indole-3-carbinol (I3C) and myo-inositol (MI) inhibit lung adenoma induced by tobacco smoke carcinogens in A/J mice. In this paper, we extended our work and examined the effects of I3C (70 or 30 micromol/g diet) and MI (56 micromol/g diet) against vinyl carbamate (VC)-induced lung adenocarcinoma by administering the agents from 1 week after the second of two injections of VC until termination of the study at week 18. The higher dose of I3C decreased multiplicities of tumors on the surface of the lung (26%, P = 0.0005), carcinoma incidence (38%), multiplicity (67%, P < 0.0001) and size (complete abolition of carcinoma with an area of >1.0 cm(2)) as well as adenoma with cellular pleomorphism (46%, P < 0.0001). The lower dose of I3C was less effective. MI decreased multiplicities of pulmonary surface tumors (20%, P = 0.0005), adenoma with cellular pleomorphism (40%, P < 0.0001) and lung adenoma (52%, P < 0.0001) and the proportion of the biggest carcinoma (carcinoma with an area of >1.0 cm(2), P < 0.05). Immunoblot analyses of lung tissues for potential target identification showed that I3C (70 micromol/g diet) inhibits IkappaBalpha degradation, nuclear factor-kappaB activation, expression of cyclooxygenase-2, phospho-Akt and fatty acid synthase (FAS) and activates caspase-3 and poly ADP ribose polymerase cleavage. The effect of MI was limited to inhibition of phospho-Akt and FAS expression. Our data show that I3C and MI inhibit lung carcinoma and provide a basis for future evaluation of these compounds in clinical trials as chemopreventive agents for current and former smokers.
Kassie
Fekadu
F
Masonic Cancer Center, Mayo Mail Code 806, Minneapolis, MN 55455, USA. kassi012@umn.edu
Kalscheuer
Stephen
S
Matise
Ilze
I
Ma
Linan
L
Melkamu
Tamene
T
Upadhyaya
Pramod
P
Hecht
Stephen S
SS
D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007294:Inositol / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives* / Q000633:toxicity; D014803:Vitamin B Complex
D016588:Anticarcinogenic Agents; D007211:Indoles; D014803:Vitamin B Complex; D014520:Urethane; D007294:Inositol; C017963:vinyl carbamate; C016517:indole-3-carbinol; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3