Cryptolepine,
matadine, and
serpentine are three indoloquinoline
alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these
alkaloids have been used in African
folk medicine in the form of
plant extracts for the treatment of multiple diseases, in particular as
antimalarial drugs. To date, the molecular basis for their diverse
biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with
DNA and their effects on
topoisomerase II. The strength and mode of binding to
DNA of the three
alkaloids were investigated by spectroscopy. The
alkaloids bind tightly to
DNA and behave as typical
intercalating agents. All three compounds stabilize the
topoisomerase II-
DNA covalent complex and stimulate the cutting of
DNA by
topoisomerase II. The
poisoning effect is more pronounced with
cryptolepine than with
matadine and
serpentine, but none of the drugs exhibit a preference for cutting at a specific base.
Cryptolepine which binds 10-fold more tightly to
DNA than the two related
alkaloids proves to be much more cytotoxic toward
B16 melanoma cells than
matadine and
serpentine. The cellular consequences of the inhibition of
topoisomerase II by
cryptolepine were investigated using the HL60
leukemia cell line. The flow cytometry analysis shows that the
drug alters the cell cycle distribution, but no sign of
drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of
DNA in cells.
Cryptolepine-treated cells probably die via
necrosis rather than via apoptosis. The results provide evidence that
DNA and
topoisomerase II are the primary targets of
cryptolepine,
matadine, and
serpentine.