Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination.

Abstract

In an extension of our earlier studies, we examined the inhibitory effects of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine (PEITC-NAC), myo-inositol (MI) and indole-3-carbinol (I3C) or 3,3'-diindolylmethane (DIM), alone and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (BaP)-induced A/J mouse lung tumorigenesis and proliferation of A549 cells and human bronchial epithelial cells (HBECs) and relevant potential mechanisms. Mice treated with NNK plus BaP and fed non-supplemented diet had 13.0 + or - 4.1 lung tumors per mouse. Dietary feeding of mice with PEITC-NAC (5 mumol/g diet), I3C (5 mumol/g diet) or MI (56 mumol/g diet), beginning at 50% in the carcinogen treatment phase, significantly reduced tumor multiplicity to 8.2 + or - 2.0, 8.4 + or - 1.5 and 6.8 + or - 1.7 tumors per mouse, respectively. In mice given combinations of the chemopreventive agents, lung tumor multiplicity was significantly reduced to 6.3 + or - 2.2, 4.9 + or - 1.8, 4.8 + or - 1.9 and 3.6 + or - 1.4 by PEITC-NAC plus I3C, PEITC-NAC plus MI, I3C plus MI or PEITC-NAC plus I3C plus MI, respectively. Post-carcinogen administration of combinations of the agents also caused significant but weaker effects. Assessment of the anti-proliferative effects of the individual agents or their combinations showed significant reductions in the proliferation of cigarette smoke condensate (CSC)-pretreated HBEC (reduction by 30-41% at 48 h and 41-58% at 72 h) and A549 cells (30-43% at 48 h and 40-59% at 72 h), but not in dimethyl sulfoxide-pretreated HBEC. Combinatorial treatment with the agents also caused marked reductions in the activation of Akt, extracellular signal-regulated kinase and nuclear factor-kappaB in lung tumor tissues, CSC-pretreated HBEC and A549 cells. In conclusion, our studies demonstrated the promise of combinations of PEITC-NAC, I3C/DIM and MI for the chemoprevention of lung carcinogenesis in current and former smokers.

• Authors: Fekadu Kassie, Tamene Melkamu, Abaineh Endalew, Pramod Upadhyaya, Xianghua Luo, Stephen S Hecht
• Journal: Carcinogenesis (Carcinogenesis) Vol. 31 Issue 9 Pg. 1634-41 (Sep 2010) ISSN: 1460-2180 [Electronic] England
• PMID: 20603442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticarcinogenic Agents
• Indoles
• N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine
• NF-kappa B
• Smoke
• Thiocarbamates
• Vitamin B Complex
• Benzo(a)pyrene
• Inositol
• indole-3-carbinol
• Proto-Oncogene Proteins c-akt
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Cysteine

Topics

• Adenocarcinoma (chemically induced, pathology, prevention & control)
• Animals
• Anticarcinogenic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Benzo(a)pyrene (toxicity)
• Bronchi (cytology, drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic
• Cells, Cultured
• Cysteine (analogs & derivatives, therapeutic use)
• Epithelial Cells (drug effects, metabolism)
• Female
• Humans
• Indoles (therapeutic use)
• Inositol (therapeutic use)
• Lung Neoplasms (chemically induced, pathology, prevention & control)
• Mice
• Mice, Inbred A
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NF-kappa B (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Smoke (adverse effects)
• Thiocarbamates (therapeutic use)
• Vitamin B Complex (therapeutic use)