In situ formation of cytotoxic metabolites by an
enzyme-catalyzed reaction is a recent approach in
cancer chemotherapy. We demonstrate that multidrug resistant human
melanoma cells (M14 ADR) are more sensitive than the corresponding wild type cells (M14 WT) to
hydrogen peroxide and
aldehydes, the products of bovine serum
amine oxidase (BSAO)-catalyzed oxidation of
spermine.
Hydrogen peroxide was mainly responsible for the loss of cell viability. With about 20%, the
aldehydes formed from
spermine contribute also to cytotoxicity. Elevation of temperature from 37 degrees C to 42 degrees C decreased survival of both cell lines by about one log unit. Pre-treatment with N1,N4-bis(2,3-butadienyl)-1,4-butanediamine (
MDL 72527), a lysosomotropic compound, sensitized cells to toxic
spermine metabolites.
MDL 72527 (at 300 microM) produced in M14 cells numerous cytoplasmic vacuoles which, however, disappeared by 24 h, even in the presence of the
drug. Mitochondrial damage, as observed by transmission electron microscopy, correlated better with the cytotoxic effects of the treatment than vacuole formation. Since the release of lysosomal
enzymes causes oxidative stress and apoptosis, we suggest that the lysosomotropic effect of
MDL 72527 is the major reason for its sensitizing effect.