Abstract
Cancer cells may rapidly acquire multidrug resistance, mainly due to the presence of adenosine
triphosphate-binding cassette transporters, epidermal growth factor receptor, or mutations in the p53
tumor suppressor gene. This work was designed to assess the cytotoxicity of the methanol crude
extracts and compounds from the fruits of Uapaca togoensis, namely, β-amyryl acetate
(1), 11-oxo-α-amyryl acetate (2), lupeol (3), pomolic acid (4),
futokadsurin B (5), arborinin (6), and 3-O-β-D-glucopyranosyl sitosterol
(7) against nine drug sensitive and multidrug-resistant cancer cell lines. The resazurin
reduction assay was used to evaluate the cytotoxicity of the fruits of U. togoensis and
compounds, whilst the caspase-Glo assay was used to detect the activation of caspase enzymes by the
fruits of U. togoensis and compound 6. Cell cycle, mitochondrial membrane potential, and
levels of reactive oxygen species were all analyzed via flow cytometry. The acridone alkoid 6
and the crude extract from the fruits of U. togoensis were active on all of the nine tested
cancer lines with IC50 values below 32 µM and 30 µg/mL, respectively. Compounds 2
and 5 showed selective activities and IC50 values below 99 µM or 42 µM,
respectively, which were obtained towards 3/9 and 6/9 tested cancer cell lines. Compound 6
displayed IC50 values below 10 µM towards seven of the nine tested cancer cell lines. The
IC50 values ranged from 3.55 µM (against CEM/ADR5000 cells) to 31.77 µM (against
CCRF-CEM cells) for alkaloid 6 and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against
CEM/ADR5000 cells) for doxorubicin. The crude extract of the fruits of U. togoensis induced
apoptosis in the CCRF-CEM leukemia cells, which was mediated by the disruption of the mitochondrial
membrane potential. Compound 6 also strongly induced apoptosis in CCRF-CEM cells and cell cycle
arrest in the G0/G1 and S phases. The crude extract from the fruits of this plant as well as aborinin
are potential antiproliferative natural products that deserve further investigation to develop novel
cytotoxic drugs to fight sensitive and otherwise drug-resistant phenotypes.
Key words
Uapaca togoensis
- Euphorbiaceae - alkaloid - arborinine - cytotoxicity - apoptosis
