Lysyl oxidase is an extracellular matrix, copper – dependent, amine oxidase that catalyzes a key crosslinking step in collagen and elastin.  This enzyme has also been shown to play a role in promoting metastasis.  The correlation between high LOX activity and cancer metastasis is strong enough that upregulated LOX activity can be used as a diagnostic marker for the severity of cancer in patients.  β – aminopropionitrile is a known potent inhibitor of lysyl oxidase; however, this inhibitor is not selective and, therefore, cannot be used as a therapeutic agent.  β – aminopropionitrile has been derivatized using aromatic sidechains, and has been used to selectively target lysyl oxidase in breast cancer cells.  The inhibitor LP – 1 – 2 in particular has been shown to reduce breast cancer cell viability with a 100 μM dose and 72 – hour incubation period.  The effect on cell viability increased with increasing amounts of inhibitor.  The selective targeting of lysyl oxidase was verified using western blot analysis and lysyl oxidase activity assays.  The activity assays showed that addition of increasing amounts of inhibitor decreased the activity of lysyl oxidase.  The highest level of inhibition detected was with lysyl oxidase isolated from cells treated with 5000 μM of LP – 1 – 2 for three days, which decreased the activity three – fold as compared to lysyl oxidase isolated from untreated cells.  Excitation - Emission matrix analysis has shown that the addition of inhibitors causes a conformational change in the structure of the enzyme and this has led to a new postulated mechanism for the binding of this inhibitor in the enzyme active - site.<br/>

Inhibition of lysyl oxidase in breast cancer cells using derivatized β – aminopropionitrile

255th National Meeting (2018)

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