Pharmacological and toxicological studies on anticancer properties of piplartine

Abstract

Piplartine is a known alkaloid/amide from Piper species with interesting cytotoxic properties. Pharmacological and toxicological studies of the anticancer properties were performed in several biological models. Piplartine presented IC50 values ranging from 1.04 to 3.03µM in tumor cell lines, while in peripheral blood mononuclear cells the IC50 was 45.24µM, suggesting a narrow selectivity for this compound. The structure-activity relationship analysis demonstrated that the presence of the α,β-unsaturated carbonyl moiety of the amide ring is an important structural requirement for cytotoxic activity. Moreover, piplartine treatment induced G2 cell cycle arrest followed by apoptosis in HL-60 cells by the intrinsic pathway. Piplartine treatment also induced DNA strand breaks in V79 cells. Its genotoxic mechanism of action seems to be similar to its cytotoxic activity. No mutagenic effect in Ames test (prokaryotic model) was observed. On the other hand, piplartine was mutagenic and recombinogenic in yeast (eukaryotic model). This can be explained due the differences in physiology between eukaryote and prokaryote DNA topoisomerase II, reflecting a possible interference of piplartine upon this enzyme activity. The genotoxicity was confirmed in vivo with piplartine increasing the micronuclei levels in treated mice. Additionally, the plasma levels of piplartine are compatible with the in vitro cytotoxicity, which leads us to propose that piplartine has in vivo direct cytotoxic properties. In antitumor assay, the combination of piplartine with 5-fluourouracil led to an in vitro and in vivo increasing of the tumor growth inhibition. In addition, hematological analysis showed leukopenia after 5-fluourouracil treatment, which was reversed by the combined use of piplartine. These data suggest that piplartine has a promising anticancer potential.