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Inhibition of lung tumor cell growth in vitro and mouse lung tumor formation by lovastatin
M A Hawk1, K T Cesen, J C Siglin
1Medical College of Ohio, Toledo 43699-0008, USA.
Abstract:
The HMG-CoA reductase inhibitor, lovastatin (LOV), has been reported to inhibit Ras farnesylation and the growth of Ras-transformed cells. Mouse lung tumors and human lung adenocarcinomas often have activating mutations in K-ras alleles. In the present study, we determined whether LOV inhibited the growth in vitro of mouse (C10, E9, LM1, LM2, and 82-132) and human (NCl-H125, H292, H441, H460, and H661) nor-transformed and neoplastically transformed lung epithelial cells and whether growth inhibition was related to cell transformation or K-ras activation. LOV inhibited the growth of mouse and human lung cells, but cell sensitivities were unrelated to neoplastic transformation or K-ras mutation. In addition, we evaluated whether LOV could inhibit the formation of lung adenomas induced by the tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. LOV was administered in the diet at 0, 40, 160, or 400 ppm ad libitum to male strain A/J mice beginning 1 week after lung tumor induction with NNK (10 mumol/mouse). Mice were euthanized 6 months later. Enumeration of lung tumors revealed that LOV did not affect tumor incidence or size, but significantly reduced tumor multiplicity in a dose-related manner. These data suggest that LOV can suppress the formation of NNK-induced lung tumors, possibly at an early promotional stage. This suppression does not appear to be related to either the presence of mutated K-ras or to changes in K-ras expression.
Insights
Lovastatin (LOV) inhibited lung cell growth but not K-ras mutation effects. LOV suppressed tobacco-related lung tumor formation in mice, suggesting early promotional stage intervention.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lovastatin (LOV), an HMG-CoA reductase inhibitor, is known to inhibit Ras farnesylation and Ras-transformed cell growth.
- Activating mutations in K-ras alleles are common in mouse lung tumors and human lung adenocarcinomas.
Purpose of the Study:
- To determine if lovastatin inhibits the in vitro growth of normal and neoplastic mouse and human lung epithelial cells.
- To investigate if lovastatin's growth inhibition is related to cell transformation or K-ras activation.
- To evaluate lovastatin's efficacy in preventing lung adenomas induced by NNK in mice.
Main Methods:
- Lovastatin was tested on various mouse and human lung cell lines.
- Cell sensitivity to lovastatin was assessed in relation to transformation status and K-ras mutation.
- Mice were administered lovastatin in their diet after NNK-induced lung tumor initiation, and tumor development was monitored.
Main Results:
- Lovastatin inhibited the growth of both mouse and human lung cells, irrespective of neoplastic transformation or K-ras mutation.
- Lovastatin did not affect lung tumor incidence or size in mice but significantly reduced tumor multiplicity in a dose-dependent manner.
- The observed suppression of NNK-induced lung tumors was not linked to K-ras mutation or expression levels.
Conclusions:
- Lovastatin demonstrates potential in suppressing the formation of NNK-induced lung tumors, likely by acting at an early promotional stage.
- The anti-tumor effect of lovastatin in this model is independent of K-ras mutation status or expression.