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Decrease of metastatogenic potential by pregraft treatment of Lewis lung carcinoma cells with proteinase and protein
Abstract:
Three synthetic irreversible enzyme inhibitors (75 microM di-iso-propylphosphorofluoridate (DFP), 310 microM N alpha-p-tosyl-L-lysine (TLCK) and 240 microM L-1-tosylamide-2-phenylethyl (TPCK) chloromethyl ketone), as well as the transition state analogue chymostatin, inhibit the development of Lewis lung adenocarcinoma (3LL) in C57 BI/6 mice, when 3LL cells are treated once and for a limited period (60 min) prior to grafting. These compounds demonstrate divergent protease specificity and, in the case of TLCK and TPCK, convergent reactivity toward the highly conserved protein kinase catalytic subunit. Using 200 microM chymostatin and low doses (25-40 microM) of the irreversible enzyme inhibitors, the antimetastatogenic effect is revealed to be specific, as primary tumor development is not affected. Although no direct experimental evidence can be forwarded, our results fit with the concept that the motile metastatogenic 3LL cells may constitute a phenotype which, in contrast to the resident cells from the primaries, responds to these enzyme inhibitors in a highly sensitive manner.
Insights
Enzyme inhibitors like DFP, TLCK, TPCK, and chymostatin specifically block Lewis lung adenocarcinoma metastasis. Pre-treatment of 3LL cells before grafting inhibits cancer cell motility, suggesting a targeted antimetastatogenic effect.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Metastasis is a complex process involving motile cancer cells.
- Enzyme inhibitors can modulate cellular functions.
- Lewis lung adenocarcinoma (3LL) is a model for studying metastasis.
Purpose of the Study:
- To investigate the effect of enzyme inhibitors on Lewis lung adenocarcinoma (3LL) metastasis.
- To determine if specific enzyme inhibitors can prevent cancer cell metastasis without affecting primary tumor growth.
Main Methods:
- Treatment of 3LL cells with di-iso-propylphosphorofluoridate (DFP), N alpha-p-tosyl-L-lysine (TLCK), L-1-tosylamide-2-phenylethyl (TPCK) chloromethyl ketone, and chymostatin.
- Grafting of treated 3LL cells into C57 BI/6 mice.
- Assessment of primary tumor development and metastatic spread.
Main Results:
- Irreversible enzyme inhibitors (DFP, TLCK, TPCK) and chymostatin inhibited 3LL metastasis when cells were treated prior to grafting.
- Low doses of inhibitors specifically affected metastasis, not primary tumor growth.
- TLCK and TPCK showed convergent reactivity toward protein kinase catalytic subunits.
Conclusions:
- Enzyme inhibitors can specifically target and inhibit cancer cell metastasis.
- Motile metastatic 3LL cells exhibit heightened sensitivity to certain enzyme inhibitors.
- This suggests a potential therapeutic strategy for preventing cancer spread.