Avaliação do potencial antitumoral dos hidrobenzofuranóides isolados das folhas da Tapirira guianensis (anacardiaceae)

Abstract

The hydrobenzofuranoids obtained from Tapirira guianensis are alkylated derivates of cyclo-hexanone, which appear to be precursors of phenolic lipids. The present study initially examined the activity of nine hydrobenzofuranoids in cell lines, where the compound SJC-8 showed the highest cytotoxicity. In later studies, the cytotoxicity of this sample was investigated with regard to the possible mechanism of action. In the MTT assay, SJC-8 showed IC50 values of 0.3 to 6.2µg/mL in a panel of cell lines. In acute toxicity assays in artemia nauplii and hemolytic activity in mouse erythrocytes, SJC-8 did not demonstrate any toxicity or hemolysis, respectively. The mechanism of action of SJC-8 was then studied. SJC-8 affected cell viability in HL-60 after an exposure period of 24h, when determined by trypan blue exclusion. At lower concentrations, there was no increase in the number of non-viable cells but only a reduction in cell proliferation (cytostatic effect). However, at the two highest concentrations, there was a decrease in the number of viable cells and increase in number of non-viable cells (cytotoxic effect), which corroborate the findings of morphologic analysis showing an increase in the number of dead cells. The cytotoxicity of SJC-8 involves the inhibition of DNA synthesis, as revealed by inhibition of BrdU incorporation into DNA and of topoisomerase 1 activity. SJC-8 was tested for genotoxicity using the comet assay in HL-60 cells, and was found to cause an increase in the frequency of DNA damage in a concentration-dependent manner, where more severe damage was seen at higher concentrations of SJC-8. The administration of SJC-8 (25 or 50 mg/kg/day) inhibited solid tumor growth in mice transplanted with sarcoma 180, by 12.3 and 59.8%, respectively. The antitumor activity of SJC-8 is attributed to inhibition of tumor cell proliferation. Histopathologic analysis showed in a reversible manner that the liver is the target of drug toxicity. In conclusion, SJC-8 has antitumor activity where it has a direct antiproliferative effect on tumor cells, and may therefore serve as a prototype for new antitumor agents.