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Lipoxygenase inhibitors prevent lung carcinogenesis and inhibit non-small cell lung cancer growth
T W Moody1, J Leyton, A Martinez
1Cell and Cancer Biology Department, National Cancer Institute, Rockville, Maryland, USA. moodyt@bprb.nci.nih.gov
Abstract:
The effects of lipoxygenase inhibitors were investigated using human lung cancer cell lines and A/J mice. By RT-PCR, 5-, 12-, and 15-lipoxygenase mRNA was detected in NSCLC cells. NDGA inhibited 5-LO activity in adenocarcinoma cell line NCI-H1264. Using an MTT assay, NDGA, MK591 and AA861 inhibited the growth of NSCLC cell lines tested with IC50 values of 3, 2, and 7 microM, respectively. Using a clonogenic assay, 10 microM NDGA significantly reduced NSCLC colony number. NDGA significantly slowed NSCLC xenograft growth in nude mice. When the tumors were excised and analyzed, nude mice treated with NDGA had significantly more apoptotic figures than did untreated tumors. A/J mice treated with urethane developed adenomas after 4 months and NDGA administration significantly reduced lung adenoma number. These data indicate that lipoxygenase inhibitors inhibit lung cancer growth and prevent lung carcinogenesis.
Insights
Lipoxygenase inhibitors show promise in combating lung cancer. These compounds effectively inhibited non-small cell lung cancer (NSCLC) growth and reduced lung adenoma formation in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lipoxygenases (LOs) are enzymes implicated in inflammation and cancer development.
- Specific LO isoforms (5-, 12-, and 15-LO) are present in non-small cell lung cancer (NSCLC) cells.
- Targeting LO pathways represents a potential strategy for lung cancer prevention and treatment.
Purpose of the Study:
- To investigate the efficacy of lipoxygenase inhibitors in inhibiting lung cancer cell growth and preventing lung carcinogenesis.
- To evaluate the effects of specific inhibitors like NDGA, MK591, and AA861 on NSCLC cell lines and in animal models.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) to detect lipoxygenase mRNA expression.
- MTT and clonogenic assays to assess the impact of inhibitors on NSCLC cell viability and proliferation.
- In vivo studies using nude mice xenografts and A/J mice models to evaluate tumor growth inhibition and chemopreventive effects.
Main Results:
- NDGA demonstrated inhibition of 5-LO activity in NSCLC cells.
- NDGA, MK591, and AA861 significantly inhibited NSCLC cell growth with low IC50 values.
- NDGA treatment reduced NSCLC colony formation, slowed xenograft tumor growth, and increased apoptosis in tumors.
- NDGA significantly decreased lung adenoma incidence in a chemical carcinogenesis model.
Conclusions:
- Lipoxygenase inhibitors effectively suppress lung cancer cell proliferation and tumor growth.
- These findings suggest that lipoxygenase inhibitors hold potential as therapeutic agents for lung cancer and as chemopreventive agents against lung carcinogenesis.