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Cytotoxicity of selected Cameroonian medicinal plants and Nauclea pobeguinii towards multi-factorial drug-resistant cancer cells
© Kuete et al. 2015
Received: 3 February 2015
Accepted: 1 September 2015
Published: 4 September 2015
Malignacies are still a major public concern worldwide and despite the intensive search for new chemotherapeutic agents, treatment still remains a challenging issue. This work was designed to assess the cytotoxicity of six selected Cameroonian medicinal plants, including Nauclea pobeguinii and its constituents 3-acetoxy-11-oxo-urs-12-ene (1), p-coumaric acid (2), citric acid trimethyl ester (3), resveratrol (4), resveratrol β-D-glucopyranoside (5) and strictosamide (6), against 8 drug-sensitive and multidrug-resistant (MDR) cancer cell lines.
The resazurin reduction assay was used to evaluate the cytotoxicity of the crude extracts and compounds, whilst column chromatography was used to isolate the constituents of Nauclea pobeguinii. Structural characterization of isolated compounds was performed using nuclear magnetic resonance (NMR) spectroscopic data.
Preliminary experiments on leukemia CCRF-CEM cells at 40 μg/mL showed that the leaves and bark extracts from Tragia benthamii, Canarium schweinfurthii, Myrianthus arboreus, Dischistocalyx grandifolius and Fagara macrophylla induced more than 50 % growth of this cell line contrary to the leaves and bark extracts of N. pobeguinii. IC50 values below or around 30 μg/mL were obtained with leaves and bark extracts of N. pobeguinii towards two and five, respectively, of the 8 tested cancer cell lines. The lowest IC50 value was obtained with the bark extract of N. pobeguinii against HCT116 (p53 −/− ) colon cancer cells (8.70 μg/mL). Compounds 4 and 6 displayed selective activity on leukemia and carcinoma cells, whilst 1–3 were not active. IC50 values below 100 μM were recorded with compound 5 on all 9 tested cancer cell lines as well as with 4 against 7 out of 8 and 6 against 2 out of 8 cell lines.
Collateral sensitivity was observed in CEM/ADR5000 leukemia cells, MDA-MB-231-BCRP breast adenocarcinoma cells (0.53-fold), HCT116 (p53 +/+ ) cells, human U87MG.ΔEGFR glioblastome multiforme cells to the methanolic bark extract of N. pobeguinii, as well as in MDA-MB-231-BCRP cells and HCT116 (p53 +/+ ) cells and U87MG.ΔEGFR cells (0.86-fold) to compound 5.
The results of this study demonstrate the cytotoxicity of six Cameroonian medicinal plants, Canarium schweinfurthii, Dischistocalyx grandifolius, Tragia benthamii, Fagara macrophylla, Myrianthus arboreus and Nauclea pobeguinii. We also demonstrated the antiproliferative potential of Nauclea pobeguinii against drug-resistant cancer cell lines. Resveratrol and its glucoside are the major cytotoxic constituents in the bark of Nauclea pobeguinii.
Investigated plants, their traditional use, chemical constituents and bioactivities
Species (family); Voucher number* and place of plant’s collection
Parts used traditionally (part used in this study and percentage yield)
Bioactive or potentially bioactive components
Canarium schweinfurthii Engl. (Burseraceae); 19652/HNC; Bangangté
Bark, seeds, fruits, leaves and roots (bark: 7.36 %)
Insecticide, dysentery, gonorrhea, coughs, chest pains, pulmonary affections, stomach complaints, food poisoning, purgative and emetic, roundworm infections and other intestinal parasites, emollient, stimulant, diuretic, skin-affections, eczema, leprosy, ulcers ; diabetes mellitus ; colic, stomach pains, pains after child birth, gale ; fever, constipation, malaria, sexually transmitted infection and rheumatism .
From oil: Limonene, phellandrenes ; bark: Triterpenes steroids, saponins, lipids and glycosides ; seeds: schweinfurthinol, p-hydroxybenzaldehyde, coniferaldehyde, p-hydroxycinnamaldehyde, ligballinol, amantoflavone ; catechol, dihydroxyphenylacetic acid, tyrosol, p-hydroxybenzoic acid, dihydroxynezoic acid, vanilic acid, phloretic acid, pinoresinol, secoisolariciresinol ; tannins, cardiacglycosides, balsams, phenols and flavonoids (Uzama et al., 2012), canarene .
Chemoprevention of cancer and other oxidative damage-induced diseases: fruit mesocarp oil extract (Atawodi, 2010) and seed kernel oil extract ; Antimycobacterial activities: leaves ; antimicrobial activities of dichloromethane, ethylacetate and ethanol extracts against gastrointestinal pathogenic bacteria .
Dischistocalyx grandifolius C.B.Clarke (Acanthaceae) 27646/SRF Cam; Mbouda
Whole plant (whole plant: 4.53 %)
Infectious diseases 
Fagara macrophylla Engl. (Rutaceae) 6173/SRF Cam; Mbouda
Bark, leaves and seeds (bark: 8.43 %; leaves: 6.81 %)
Alkaloids: tembetarineoblongine, magnoflorine, arborinine, nitidine, dihydronitidine, xanthoxoline, 1-Hydroxy-3-methoxy-N-methyl-acridone, N-(4 hydroxyphenethyl)octacosanamide, N-(4-hydroxyphenethyl)hexacosanamide, N-(4-hydroxyphenethyl)decanamide, N-vanilloyltyramine, and N-[O-docosanoylvanilloyl]tyramine, flavonoid: hesperidin [53–56]
Antiplasmodial :bark ; Antifeedant: xanthoxoline and 1-hydroxy-3-methoxy-N-methyl-acridone, arborinine, tembetarine and magnoflorine against Spodoptera frugiperda, S. littoralis and S. frugiperda ; Low cytotoxicity: seeds extract towards leukemia CCRF-CEM and CEM/ADR5000 cells lines and pancreatic cancer MiaPaCa-2 cell line ; Antitumor: nitidine chloride and 6-methoxy-5,6-dihydronitidine 
Myrianthus arboreus P.Beauv. (Moraceae) 55499/HNC; Bangangté
Bark, leaves (bark: 7.68 %; leaves: 10.37 %)
Dysentery, diarrhea, vomiting, analgesic, antipyretic, heart troubles, pregnancy complications, dysmenorrheal, incipient hernia, boils, toothache, bronchitis, sore throat ; headaches, swellings and tumours, diabetes ; stomach disorders .
Nauclea pobeguinii (Pobég. ex Pellegr.) Merr. ex E.M.A. (Rubiaceae) 32597/HNC; Mbouda
Bark, leaves, roots (bark: 6.55 %; leaves: 6.31 %)
Antiplasmodial: extract and 3-O-β-fucosylquinovic acid and 3-ketoquinovic acid against Plasmodium falciparum .
Tragia benthamii Bak. (Euphorbiaceae) 23329/SRF Cam; Mbouda
Whole plant (whole plant: 5.18 %)
Sores, swollen armpit, abortifacient, child delivery promoter .
Tannins, saponins, flavonoids, alkaloids, flavonoids .
Antiplasmodial: against Plasmodium berghei .
Vacuum liquid chromatography (VLC), column chromatography (CC) and thin layer chromatography (TLC) were performed on silica gel 60 (particle size 90 % <45 mm), 200–300 mesh silica gel, and silica gel GF254 (Merck), respectively. Melting points (m.p.) were measured by an Electro thermal IA 9000 digital melting point apparatus (Electro thermal) and are uncorrected. The NMR data were recorded with a Bruker DRX-400 MHz (Bruker). LR-EI-MS were recorded with JEOL mass spectrometer instrument (JEOL). The purity of the molecules was determined by HPLC (Shimadzu HPLC system), using a LiChrospher100 RP-18 (250 × 4 mm, 5 μM) column and MeOH-H2O (6:4 and 8:2)/0.1 TEA as mobile phase with detection at 273 nm.
Doxorubicin 98.0 % from Sigma-Aldrich was provided by the University Pharmacy of the Johannes Gutenberg University-Mainz and dissolved in PBS (Invitrogen) at a concentration of 10 mM. Geneticin >98 % (72.18 mM) was obtained from Sigma-Aldrich.
The plant materials used in this study were the bark of Canarium schweinfurthii Engl. (Burseraceae), the whole plant of Dischistocalyx grandifolius C.B.Clarke (Acanthaceae) and Tragia benthamii Bak. (Euphorbiaceae), the bark and leaves of Fagara macrophylla Engl. (Rutaceae), Myrianthus arboreus P.Beauv. (Moraceae), Nauclea pobeguinii (Pobég. ex Pellegr.) Merr. ex E.M.A. (Rubiaceae). The plant materials were collected in March and April 2013 in Bangangté and Mbouda (west region of Cameroon). They were identified at the National Herbarium in Yaoundé, Cameroon and compared with voucher specimens formerly kept under the registration number (Table 1).
Air-dried plant material (3 kg for the bark of Nauclea pobeguinii and 1 kg for other samples) was powdered and extracted with methanol (MeOH; 10 L for the bark of Nauclea pobeguinii and 3 L for other samples) for two days. The organic solution was concentrated in vacuo to yield a paste (crude extract). The yield of each extract was determined (Table 1) and the samples were kept at 4 °C until further use.
Isolation of compounds from the bark of nauclea pobeguinii
The crude extract (80 g) was further poured onto distilled water and separated with dichloromethane (DCM) (A), ethyl acetate, EA (B), and n-butanol, n-BuOH (C) under the non-miscible liquid-liquid process. The concentration in vacuo of each organic portion afforded fractions A (42 g), B (12 g), and C (28 g), respectively. A column (5 × 60 cm) was used for the purification of fraction A. Silica gel (160 g) column chromatography was prepared and A was eluted under gradient conditions with pure (100 %) hexane (hex) and EA affording 75 fractions of 100 mL each. A colorless powder (1, 10 mg) was obtained from sub-fractions 15–20, while a brown oil (2, 3.5 mg) was isolated from sub-fractions 25–27. A colorless sticky gum (3, 11.2 mg) was further obtained from sub-fractions 50–63. Moreover, fraction B was loaded onto a silica gel (50 g) column (2 cm × 50 cm) and the column was eluted with DCM/EA (98:2, v/v) to give exclusively 2.1 mg of a brownish solid (4). Fraction C was also loaded onto the same column as A using 150 g of silica gel. The column was eluted with pure DCM/MeOH under gradient condition to afford 90 fractions. Sub-fractions 2–10 afforded 5 mg of compound 4, while sub-fractions 30–40 pooled together based on TLC profile gave a colorless solid (5, 5 mg). Similarly, a yellow solid (6, 20 mg) was obtained after filtration of sub-fractions 60–75. These sub-fractions were pooled together based on the TLC profile, after complete evaporation, the solid residue was recrystallized with acetone to give again 6 (15 mg).
Structural characterization of isolated compounds
The cell lines used in the present work, their origins and their treatments were previously reported [18, 19]. They include drug-sensitive leukemia CCRF-CEM cells, its multidrug-resistant subline CEM/ADR5000 cells [3, 20, 21], breast cancer MDA-MB-231-pcDNA3 cells, its resistant subline MDA-MB-231-BCRP clone 23) cells , colon HCT116 (p53 +/+ ) cancer cells, its knockout clones HCT116 (p53 −/− ), glioblastoma U87MG cells, its resistant subline U87MG.ΔEGFR cells and normal AML12 hepatocytes [14, 15, 19, 23]. The CCRF-CEM and CEM/ADR5000 leukemia cells were maintained in RPMI 1640 medium (Invitrogen) supplemented with 10 % fetal calf serum in a humidified 5 % CO2 atm at 37 °C. Breast cancer cells, transduced with control vector (MDA-MB-231-pcDNA3) or with cDNA for the breast cancer resistance protein BCRP (MDA-MB-231-BCRP clone 23), were maintained under standard conditions as described above for CCRF-CEM cells. Human wild-type HCT116 (p53 +/+ ) colon cancer cells as well as knockout clones HCT116 (p53 −/− ) derived by homologous recombination were a generous gift from Dr. B. Vogelstein and H. Hermeking (Howard Hughes Medical Institute, Baltimore, MD). Human glioblastoma multiforme U87MG cells (non-transduced) and U87MG cell line transduced with an expression vector harboring an epidermal growth factor receptor (EGFR) gene with a genomic deletion of exons 2 through 7 (U87MG.ΔEGFR) were kindly provided by Dr. W. K. Cavenee (Ludwig Institute for Cancer Research, San Diego, CA). MDA-MB-231-BCRP, U87MG.ΔEGFR and HCT116 (p53 −/− ) were maintained in DMEM medium containing 10 % FBS (Invitrogen) and 1 % penicillin (100 U/mL)-streptomycin (100 μg/mL) (Invitrogen) and were continuously treated with 800 ng/mL and 400 μg/mL geneticin, respectively. Normal AML12 heptocytes were obtained from the American Type Culture Collection (ATCC, USA). The above medium without geneticin was used to maintain MDA-MB-231, U87MG, HCT116 (p53 +/+ ) and AML12 cell lines. The cells were passaged twice weekly. All experiments were performed with cells in the logarithmic growth phase.
Resazurin reduction assay
The cytotoxicity of the tested samples was performed by resazurin reduction assay as we previously described [14, 15, 18, 19, 24, 25]. Briefly, adherent cells at 1 × 104 cells were allowed to attach overnight and were then treated with different concentrations of the studied samples. For suspension cells, aliquots of 2 × 104 cells per well were seeded in 96-well-plates in a final volume of 200 μL. Extracts and compounds were prior diluted in DMSO and tested in a final concentration below 0.1 % (A final concentration of 0.1 % DMSO was used as negative control and did not show any effect on cell growth). After 72 h incubation and resazurin (Sigma-Aldrich, Schnelldorf, Germany) staining, fluorescence was measured on an Infinite M2000 Pro™ plate reader (Tecan, Crailsheim, Germany) using an excitation wavelength of 544 nm and an emission wavelength of 590 nm. Each assay was done at least two times, with six replicates each. IC50 values represent the sample concentration required to inhibit 50 % of cell proliferation and were calculated from a calibration curve by linear regression using Microsoft Excel.
Results and discussion
Compounds were identified as 3-acetoxy-11-oxo-urs-12-ene C32H50O3 (1; m.p. 282.1-283.4 °C; m/z: 482.4; purity: 90 %), p-coumaric acid C9H8O3 (2; m/z: 164.0; purity: 97 %), citric acid trimethyl ester C9H14O7 (3; m/z: 234.0; purity: 97 %), resveratrol C14H12O3 (4; m/z: 228.1; purity: 98 %), resveratrol β-D-glucopyranoside C20H22O8 (5; m/z: 390.1; purity: 95 %), and strictosamide C26H30N2O8 (6; m/z: 498.2; purity: 96 %) . The irido-indole alkaloid strictosamide (6, 35 mg) was the major constituent of the bark extract. This is in accordance with previous studies reporting 6 as the main compound isolated from the bark methanolic extract of Nauclea pobeguinii harvested in Democratic Republic of Congo . However, Xu et al.  also identified several other alkaloids as minor constituents of the bark extract, such as naucleidinic acid and 19-O-methyl-3,14-dihydroangustoline, naucleidinal, magniflorine, naucleofficine D, 3,14-dihydroangustoline, strictosidine, desoxycordifoline, 3a,5a-tetrahydrodeoxycordifoline lactam, and a phenol kelampayoside A. These compounds were not isolated in our sample from Cameroon. In addition, compounds 1–5 reported in this study were also not found in the plant harvested in Congo. This could either be due to the isolation techniques used or to the environmental variation that influences the concentration of the minor constituents synthesized by the Nauclea pobeguinii. strictosamide (6) was obtained as the major constituent isolated from the methanolic extract in both cases.
Cytotoxicity of extracts and compounds from Nauclea pobeguinii towards sensitive and drug-resistant cancer cell lines and normal cells as determined by the resazurin assay
Tested samples, IC50 values and degrees of resistance (in bracket)
Crude extracts and IC50 values (μg/mL)
IC50 values of compounds (μM)
IC50 values of doxorubicin (μM)
14.62 ± 1.23
25.84 ± 2.16
28.15 ± 1.32
25.08 ± 2.48
77.10 ± 5.87
0.20 ± 0.06
11.56 ± 0.85 (0.80)
25.55 ± 1.63 (0.99)
57.43 ± 3.67 (2.04)
39.87 ± 2.91 (1.59)
195.12 ± 14.30 (975.60)
37.00 ± 2.91
64.75 ± 5.08
19.90 ± 1.45
97.64 ± 7.60
1.10 ± 0.28
19.79 ± 2.13 (0.53)
59.55 ± 4.21 (0.92)
22.93 ± 1.64 (1.15)
95.59 ± 8.17 (0.98)
78.26 ± 6.22 (<0.97)
7.83 ± 0.47 (7.12)
HCT116 (p53 +/+ )
16.19 ± 1.16
32.78 ± 2.67
73.65 ± 5.67
63.77 ± 4.61
1.41 ± 0.29
HCT116 (p53 −/− )
8.70 ± 0.68 (0.54)
19.39 ± 1.34 (0.59)
47.03 ± 4.94 (0.74)
4.06 ± 0.07 (2.88)
69.44 ± 4.34
76.59 ± 4.92
55.64 ± 3.73
1.06 ± 0.15
32.78 ± 2.79 (0.47)
63.90 ± 4.77 (>1.60)
28.45 ± 2.06 (0.37)
47.59 ± 3.29 (0.86)
6.11 ± 0.57(5.76)
The development of MDR in cancer cells either through ABC transporters , the epidermal growth factor receptor (EGFR) [2–4], or the tumor suppressor p53 gene  represents a major hurdle in chemotherapy. The discovery of new compounds with activity against MDR is hence very important in the ongoing fight against malignancies. In the present study, we used cell lines possessing all these resistance mechanisms to investigate multi-factorial drug resistance. The degrees of resistance were determined as the ratio of IC50 value of the resistant cell line to that of the corresponding parental sensitive counterpart (Table 2). Compared to their corresponding sensitive cell lines, collateral sensitivity in resistant cells (hypersensitivity) was observed in P-glycoprotein-overexpressing CEM/ADR5000 cells (degree of resistance 0.80-fold), BCRP-overexpressing MDA-MB-231-BCRP cells (0.53-fold), p53 HCT116 (p53 −/− ) knockout cells (<0.54-fold) and epidermal growth factor receptor-overexpressing U87MG.ΔEGFR cells (0.47-fold) to the bark extract of N. pobeguinii. Collateral sensitivity was also found in HCT116 (p53 −/− ) cells (0.74-fold) and U87MG.ΔEGFR cells (0.86-fold) to compound 5.
The obtained data indicates that the stilbene resveratrol glucoside 5 and its aglycon 4 displayed slightly different degrees of activity on the cancer cell lines studied. This shows that glucosylation may positively (especially in leukemia cells) influence the cytotoxic activity. In fact, resveratrol glucoside 5 was more active than its aglcon 4 on the two tested leukemia cells. However, in carcinoma cell lines, the cytotoxicity of compounds 4 and 5 varied from one cell lines to other, none of two being more active than other one in all the solid cancer cell lines tested. To the best of our knowledge, this phytochemical and cytotoxicity study of the crude bark and leaf extracts as well as compounds 1–3 and 5 of Nauclea pobeguinii towards multifactorial drug resistant cancer lines is being reported here for the first time. Though strictosamide (6) is known to be the main constituent  of this plant, the present study suprisingly showed that it was not the most cytotoxic component of the extracts against the studied cancer cell lines. The best activities were reported with stilbenes namely resveratrol (4) and it glycoside resveratrol β-D-glucopyranoside (5). Compound 4 is a well known cytotoxic agent [37–39]. It is reported to suppress the proliferation of SKBR-3 breast cancer cells by inhibiting fatty acid synthase signaling pathway . Compound 4 also alleviates the PI3K/Akt/mTOR signaling in breast cancer SKBR-3cells by down-regulation of Akt phosphorylation and up-regulation of PTEN expression . Besides, compound 4 reportedly reverses MDR of the MCF-7/DOX breast cancer cells . In the present study, compound 4 was most effective (IC50 < 23 μM) against MDA-MB231 breast adenocarcinoma cells and their drug-resistant, MDA-MB231/BCRP. These data are in accordance with previous reports and consolidates the potential cytotoxicity of 4 against breast cancer cells.
In conclusion, we demonstrate the cytotoxic potential of six Cameroonian medicinal plants, Canarium schweinfurthii, Dischistocalyx grandifolius, Tragia benthamii, Fagara macrophylla, Myrianthus arboreus and Nauclea pobeguinii. We also demonstrated the cytotoxic potential of leaves and bark of Nauclea pobeguinii against sensitive and MDR cancer cell lines. We further identified resveratrol and its β-glucoside as major cytotoxic constituents of the bark of Nauclea pobeguinii. The bark and leaves extracts of Nauclea pobeguinii are potential cytotoxic botanicals that deserves more investigations to develop novel cytotoxic phytomedicines against drug-resistant cancers.
The authors acknowledge the Cameroon National Herbarium (Yaoundé) for the plant identification. VK is very grateful to the Alexander von Humboldt Foundation for 18 months fellowship in Germany through the ''Georg Foster Research Fellowship for Experienced Researcher'' program.
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