Cytotoxic Compounds from the Fruits of Uapaca togoensis towards Multifactorial Drug-Resistant Cancer Cells

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.

Potential of Central, Eastern and Western Africa Medicinal Plants for Cancer Therapy: Spotlight on Resistant Cells and Molecular Targets

“…(Araliaceae) (Kuete et al, 2014e) and Uapaca togoensis Pax. (Kuete et al, 2015e). Compounds acting in p53 knockout cancer cells included: alkaloid, 48 (Kuete et al, 2015b), benzophenone, 26 (Kuete et al, 2013d), flavonoids, 12 (Kuete et al, 2016c), 27 (Kuete et al, 2015c), laburnetin ( 32 ) (Kuete et al, 2016c), 38 (Kuete et al, 2015d), isoflavonoids, 9 (Kuete et al, 2014c), 11 (Kuete et al, 2014c), 16 (Kuete et al, 2014c), 29 (Kuete et al, 2014d), 44 (Kuete et al, 2014c), neobavaisoflavone ( 35 ) from Erythrina senegalensis DC (Kuete et al, 2014d), lignan, 23 (Kuete et al, 2016c), xanthones, 10 (Kuete et al, 2013b), and 22 (Kuete et al, 2016c).…”

“…(Kuete et al, 2016e) and Uapaca togoensis Pax. (Kuete et al, 2015e), the Fabaceae, Albizia adianthifolia (Schum.) (Kuete et al, 2016e) and Erythrina sigmoidea Hua (Kuete et al, 2016a), the Moraceae, Dorstenia psilurus Welwitch (Pieme et al, 2013), the Passifloraceae, Passiflora edulis Sims (Kuete et al, 2016b), the Piperaceae, Piper capense L.f. (Kuete et al, 2013c), the Poaceae, Imperata cylindrica Beauv.…”

“…(Kuete et al, 2015f), Pachypodanthium staudtii Engl & Diels (Kuete et al, 2016b) and Uapaca togoensis Pax. (Euphorbiaceae) (Kuete et al, 2015e) (Table 1). Compounds exerting similar activity included: alkaloids, 47, 48 , and 49 (Kuete et al, 2015b), diterpene, galanal A ( 2 ) isolated from Aframomum arundinaceum (Oliver & Hanbury) K. Schum (Kuete et al, 2014a), benzophenone, isogarcinol ( 28 ) from Hypericum lanceolatum Lam.…”

“…In traditional medicine, the plant is used as antiemetic, lotion for skin disorders (Mengome et al, 2010), remedy for pneumonia, cough, fever, rheumatism, vomiting, epilepsy (Kone et al, 2006) and bacterial diseases (Kone et al, 2004). The cytotoxicity of the methanol extract from fruit was reported toward CCRF-CEM cells (IC 50 : 4.23 μg/mL), CEM/ADR5000 cells (IC 50 : 4.44 μg/mL), MDA-MB-231- pcDNA cells (IC 50 : 25.85 μg/mL), MDA-MB-231- BCRP cells (IC 50 : 4.17 μg/mL), HCT116 ( p53 +/+ ) cells (IC 50 : 3,69 μg/mL), HCT116 ( p53 −/− ) cells (IC 50 : 3.09 μg/mL), U87MG cells (IC 50 : 8.01 μg/mL), U87MG.Δ EGFR cells (IC 50 : 8.68 μg/mL), and HepG2 cells (IC 50 : 19.90 μg/mL) (Kuete et al, 2015e). This extract induced apoptosis in CCRF-CEM cells mediated by MMP loss (Kuete et al, 2015e).…”

Antimalarial Activity of the n-Butanol Fraction of Uapaca togoensis (Pax) Stem Bark in Mice

“…19 Isolated compounds from the fruits of U. togoensis namely; β-amyryl acetate, 11-oxo-α-amyryl acetate, lupeol, pomolic acid, futokadsurin B, arborinin, and 3-O-β-D-glucopyranosyl sitosterol have demonstrated strong cytotoxic activity on many drugresistant and sensitive cancer cell lines. 20 The methanol stem bark extract of the plant has been reported to posess antimicrobial activity. 18 The ethyl acetate fraction of the stem bark also exhibited antiplasmodial, analgesic and anti-inflammatory properties.…”