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Inhibition of NNK-induced lung tumorigenesis by modulators of NNK activation
1Division of Environmental Health Sciences, Ohio State University School of Public Health, Columbus, USA.
Abstract:
NNK, a tobacco-specific nitrosamine, is a potent lung carcinogen in A/J mice. One possible mechanism of reducing NNK-induced lung tumorigenesis is decreased delivery of NNK to lung as a result of enhanced hepatic CYP activity. Pretreatment with 13C, a known CYP inducer, results in inhibition of tumor multiplicity, decreased DNA adducts in lung, and increased DNA adducts in liver, due to induction of hepatic activation of NNK. A more preferable means of inhibition of NNK tumorigenesis involves direct inhibition of CYP enzymes responsible for NNK activation in lung. The arylalkyl isothiocyanates PEITC, PPITC, PBITC, PPeITC, and PHITC are effective inhibitors of NNK-induced lung tumorigenicity and DNA adduction. PEITC inhibits NNK-induced lung tumors at a dose of 5 mumol/day, but not at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC are considerably more potent inhibitors than PEITC, resulting in significant reductions in tumor multiplicity at doses of 0.2 mumol/day. For these compounds, there is a good correlation between inhibition of tumor multiplicity and inhibition of pulmonary O6-methylguanine. LIM, previously shown by Wattenberg to be an effective inhibitor of NNK-induced lung tumors, and other monoterpenes are good inhibitors of NNK activation in vitro or in vivo. Thus, compounds that modulate the metabolic activation of NNK can be potent inhibitors of NNK tumorigenesis.
Insights
Certain compounds can inhibit lung cancer caused by NNK, a tobacco carcinogen. Isothiocyanates and monoterpenes show promise by blocking NNK activation in the lungs, reducing tumor development.
Area of Science:
- Biochemistry
- Toxicology
- Carcinogenesis
Background:
- NNK (nicotine-derived nitrosamine ketone) is a potent lung carcinogen.
- CYP enzymes play a critical role in NNK activation and tumorigenesis.
- Modulating NNK metabolic activation is a potential strategy for cancer prevention.
Purpose of the Study:
- To investigate the inhibitory effects of various compounds on NNK-induced lung tumorigenesis.
- To evaluate the efficacy of arylalkyl isothiocyanates and monoterpenes in preventing NNK-induced lung tumors.
- To correlate the inhibition of tumor multiplicity with the inhibition of NNK DNA adduction.
Main Methods:
- A/J mice were used to study NNK-induced lung tumorigenesis.
- Compounds like 13C, PEITC, PPITC, PBITC, PPeITC, PHITC, and LIM were administered.
- Tumor multiplicity, DNA adducts in lung and liver, and O6-methylguanine levels were measured.
Main Results:
- Pretreatment with 13C (CYP inducer) inhibited tumor multiplicity and lung DNA adducts.
- Arylalkyl isothiocyanates (PPITC, PBITC, PPeITC, PHITC) were potent inhibitors of NNK-induced lung tumorigenicity and DNA adduction at low doses.
- LIM and other monoterpenes also demonstrated inhibitory effects on NNK activation.
Conclusions:
- Compounds that modulate NNK metabolic activation can effectively inhibit NNK-induced lung tumorigenesis.
- Specific arylalkyl isothiocyanates and monoterpenes are promising candidates for preventing tobacco-related lung cancer.
- Targeting CYP-mediated NNK activation in the lung offers a viable strategy for cancer chemoprevention.