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Cytotoxic activity of acetogenins and styryl lactones isolated from Goniothalamus undulatus Ridl. root extracts against a lung cancer cell line (COR-L23).

ABSTRACT

An investigation of the chemical constituents in a dichloromethnae extract of Goniothalamus undulatus root led to the isolation of three known styryl lactones (5-acetoxyisogoniothalamin oxide, O-acetylaltholactone and altholactone), and four known annonaceous acetogenins (annonacin, cis-annonacin, goniothalamicin and cis-goniothalamicin). These compounds were subjected to a sulphorhodamine B (SRB) cytotoxicity assay against human large cell lung carcinoma (COR-L23), and normal human fetal fibroblast (MRC-5), cell lines. The isolated acetogenins showed higher cytotoxic activity against COR-L23 compared to the styryl lactones, with [IC.sub.50] values in the range of 0.5-1.7 [micro]M and 7.4-15.4 [micro]M, respectively. A similar pattern of cytotoxicity was also observed against the other cell line (MRC-5); acetogenins [IC.sub.5o] values were in the range of 11.8-31.4 [micro]M, and those for styryl lactones were in the range of 48.7-102.8 [micro]M. This is the first report of a bioassay-guided isolation of chemical constituents from G. undulatus and on cytotoxic studies of the isolated compounds using these particular lung cancer cell lines.

[C] 2010 Elsevier GmbH. All rights reserved.

ARTICLE INFO

Keywords:

Goniothalamus undulatus

Styryl lactones

Acetogenins

Cytotoxic activity

Introduction

The genus Goniothalamus Hook.f. & Thomas (Family Annonaceae) consists of about 160 species of shrubs and small to large trees. These species are widely distributed in lowland and submontane tropical forests in Southeast Asia (Saunders 2002; Wiart 2007; Saunders and Chalermglin 2008). Only six species of Goniothalamus have been used as ethnomedicines in Asia. In Thailand, the essence derived from boiling the root of G. macrophyllus is used to "nourish the blood and invigorate the body" (Thonghom 1993). A water decoction of the stem bark of G. laoticus is still being used traditionally as a tonic and febrifuge by the local people in the northeastern part of Thailand (The National Identity Office 2000). In Malaysia, a decoction of the roots of this plant is used as an abortifacient, and interestingly also to aid recovery from childbirth. A decoction of the leaves is used for "steaming the body" to allay fever (Wiart 2007). The roots of G. tapis are used to prepare an abortifacient, or to treat typhoid fever (Wiart 2007). In Taiwan, extracts of the seed of G. amuyon have been used for the treatment of edema and rheumatism (Wu et al. 1991) The stem bark of G. dolichocarpus is burnt to repel insects, especially mosquitoes (Goh et al. 1995). The roots of G. giganteus are used as abortifacients and to treat colds and reduce swellings (Wiart 2007). A sound pharmacological basis for these ethnomedical uses of Goniothalamus species has not been reported.

Insofar as phytochemical and pharmacological studies are concerned, only 22 species out of the 160 species of the genus Goniothalamus have to date been investigated (Wiart 2007). These studies have resulted in the isolation and identification of a variety of compounds; acetogenins (Jiang and Yu 1997), alkaloids (Omar et al. 1992), azaanthraquinones (Din et al. 1990) naphthoquinones (Soonthornchareonnon et al. 1999), Styryl lactone (Hisham et al. 2003), benzenoid and styrene derivatives (Fang et al. 1990), terpenoids and flavonoids (Seidel et al. 2000) and steroids (Talapatra et al. 1988). These several compounds possess a variety of pharmacological and antimicrobial properties. The primary reason for the flurry of scientific investigations on Goniothalamus species in the last decade is because the acetogenins and styryl lactones have clearly been demonstrated to have remarkable cytotoxic and antitumor properties. Both these two classes of compounds, ubiquitous in the genus Goniothalamus, are more selective inhibitors of cancer than normal cell lines. It is of interest that both these classes of compounds appear to selectively affect the mitochondrial membrane and/or the mitochondrial respiratory systems (Yang et al. 2000; Ndob et al. 2009) of cancer cell lines, making them interesting lead compounds for the development of new cancer chemotherapeutic drugs.

In Thailand, 25 species of the genus are recognized (Saunders and Chalermglin 2008), and more than half of these are found in the southern provinces of the country (Chalermkglin 2001). There is very little ethno-medical data on the majority of these 25 species, and phytochemical studies have only been reported for G. giganteus, G. tenuifolius, G. macrophyllus, G. laoticus. In order to fully utilize Thailand's natural resources, there is a concerted effort to promote further research on these 25 species of Goniothalamus. We have recently reported on the phytochemical and biological studies on one of these species, G. macrophyllus that is used medicinally by certain local ethnic groups (Wattanapiromsakul et al. 2005).

In a preliminary screening program for cytotoxic constituents in species of Goniothalamus found in southern Thailand, leaves twigs and roots of four species (G. macrophyllus, G. tapis, G. giganteus and G. undulatus) were collected. The crude methanolic extracts of these plant parts were subjected to the sulphorhodamine B (SRB) cytotoxicity assay against three types of cancer cell lines (HepG2, MCF-7 and COR-L23). The preliminary results (unpublished data) indicated that the root of G. undulatus exhibited potent cytotoxicity against these cancer cell lines (range of [IC.sub.50] values, <1 [micro]g/ml to 7.5 [micro]g/ml).

In a continuation of our phytochemical study on the genus Goniothalamus, we now describe herein the bioassay-guided fractionation of cytotoxic chemical constituents extracted from the roots of the species G. undulatus, using the SRB cytotoxic assay against human large cell lung carcinoma (COR-L23) and normal human fetal fibroblast (MRC-5) cell lines. Currently there is no recognized ethnomedical data for G. undulatus; and this is the first report on the phytochemical and cytotoxic studies of this species using these particular cell lines.

Material and methods

General experimental procedures

[.sup.1]H (500 MHz) and [.sup.13]C (125 MHz) NMR spectra were recorded on a Varian Unity Inova 500 MHz NMR spectrometer using [CDC1.sub.3] as solvent. Mass spectra were measured on a Waters 2690-LCT Alliance-Micromass and Thermofinnigan MAT 95 XL mass spectrometers. IR spectra were recorded on a Jasco IR-810 infrared spectrometer (using KBr disks). UV spectra were obtained in methanol on a Hewlett Packard 8452A diode array spectrophotometer. The optical rotations were determined on a Jasco P-120 polarimeter. High performance liquid chromatography (HPLC) separations were performed with a Waters 600E multisolvent delivery system with a tunable absorbency detector (Waters 484) and a Rheodyne 7125 injector port. Silica gel 60 (Merck, 40-63 [micro]m) and Sephadex[R] LH-20 (Sigma-Aldrich, 25-100 [micro]m) were used for column chromatography. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 aluminium sheets (250 [micro]m thickness)

Plant material

The roots of G. undulatus were collected in October 2006 from Khao Poo--Khao Ya National Park located in Si Banpot District, Phatthalung Province, southern Thailand. The specimens were identified by Asst. Prof. Dr. Choathip Purintavaragul, Department of Biology, Faculty of Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand. A voucher specimen (number SKP 011072101) has been deposited at the Herbarium in the Department of Pharmacognosy and Pharmaceutical Botany, Prince of Songkla University.

Preparation of plant extracts

The harvested roots were washed, cut into small pieces (1 cm), oven-dried at 50[degrees]C and ground into a fine powder. The powdered roots (1.04 kg) were macerated in hexane, and then extracted sequentially by maceration with dichloromethane and methanol. The solvents were removed using a rotary evaporator (45[degrees]C) to obtain three crude extracts: hexane extract (3.0 g), dichloromethane extract (30.3 g) and methanol extract (33.6g). The hexane and dichloromethane root extracts showed cytotoxic activities against COR-L23 cell lines, with [IC sub 50] values of 13.70 and 2.53 [micro]g/mL respectively, while the methanol root extract was shown to be inactive.

Isolation and purification of cytotoxic constituents from G. undulatus

The dichloromethane extract (18.4 g) was fractionated by vacuum liquid chromatography (VLC) over a silica gel column, eluted with stepwise-gradient solvents starting with hexane then 20% ethyl acetate in methanol. Eluents were combined into 7 fractions (F1-F7) on the basis of TLC analysis. Each of these seven fractions were checked for cytotoxic activity against the COR-L23 cancer cell line. F4 (0.4 g) showed the highest activity against COR-L23 ([IC.sub.50] = 2.19 [micro]g/ml); F5(l.3 g)and F7(14.4 g)also showed good cytotoxic activity ([IC.sub.50] = 6.16 and 6.82 [micro]g/ml, respectively).

F4 (0.4 g) was further fractionated by column chromatography on silica gel with hexane: dichloromethane (3:7, v/v) as the mobile phase, to obtain compound 1 (8.5 mg). F5 (1.3 g) was also fractionated using a similar chromatographic technique with hexane: dichloromethane: ethyl acetate (2:3:1, v/v) as the mobile phase, to obtain compounds 2 (9.0 mg) and 3(31.5 mg).

Compounds 4-7 (30.2, 13.1, 11.3 and 6.3 mg, respectively) were isolated from F7 (0.66 g) using a semi-preparative HPLC RP-C18 column (Phenomenex[R][R], lO [micro]m, 250 x 10 mm; distilled water: acetonitrile, 20:80 (v/v), a flow rate of 3.0 ml/min). Retention times of compounds 4-7 were 23.6, 24.7, 31.8 and 33.1 min, respectively.

Spectroscopic properties of isolated compounds

The spectroscopic data of all the isolated compounds were identical to those reported previously in the literature. Compound 1: 5-acetoxyisogoniothalamin oxide (Hasan et al. 1994); compound 2; O-acetylaltholactone (Peris et al. 2000); compound 3: altholactone (El-Zayat et al. 1985); compound 4: annonacin (Rieser et al. 1996; Hu et al. 2001; Kim et al. 2001); compound 5: cis-annonacin (Rieser et al. 1996); compound 6: goniothalamicin (Rieser et al. 1996); and compound 7; cis-goniathalamicin (Rieser et al. 1996).

In vitro assay for cytotoxic activity

Cell lines

The extracts were investigated for their cytotoxic activity against a human large cell lung carcinoma COR-L23 and a normal human fetal fibroblast MRC-5 cell line. These were prepared and kindly provided by Dr. P. Twentyman and Dr. P. Rabbitts of the MRC Clinical ONcology & Radiotherapeutics Unit, Cambridge, UK. These cells were cultured in RPMI 1640 medium supplemented with 10% heated fetal bovine serum (FBS), 1% of 2 mM L-glutamine, 50 IU/ml penicillin and 50 [micro]g/ml streptomycin (Keawpradub et al. 1999). The optimal plating densities for each cell line were determined (1 x [10.sup.3] and 5 x [10.sup.3] cells/well for COR-L23 and MRC-5, respectively) to ensure exponential growth throughout the experimental period, and to ensure a linear relationship between absorbance at 492 nm and cell number when analysed by the sulphorhodamine B (SRB) assay.

Cytotoxicity assay

Initially, the cells were washed with magnesium and calcium-free phosphate buffered saline (PBS) (Oxoid Ltd., UK). The PBS was then decanted and the cells detached with 0.025% trypsin-EDTA (Sigma-Aldrich). Fresh PBS was then added to a volume of 50 ml. The cell pellet, obtained after centrifugation, was resuspended in 10 ml of medium. Viable cell densities were determined by trypan blue exclusion in a heamocytometer, and the cell suspensions were then diluted to give the previously-determined optimal plating densities for each cell type. These cell suspensions (100 [micro]l/well) were seeded in 96-well microtiter plates and incubated at 37 [degrees]C for 24 h to allow cell attachment. These cells were then treated with the crude extracts or pure compounds dissolved in dimethylsulfoxide. Vincristine sulphate (Sigma-Aldrich) was used as a positive control. Each extract (50[micro]g/ml) was tested initially against the COR-L23 cell line. Extracts that gave less than 20% cell survival after a 72 h exposure time were considered to be active. The active extracts or pure compounds were then systematically investigated for cytotoxicity against both cell lines and [IC.sub.50] values determined. Each active extract was diluted in the growth medium to produce 8 concentrations (0.1. 0.5, 1, 5, 10, 25, 50, 100 [micro]g/ml). These solutions (100 [micro]1/well) (n = 6 for each concentration) were added to the wells. The final dilution used for treating the cells contained not more than 1% of the initial solvent. All plates were incubated for 72 h. At the end of the exposure time, the medium was removed, the cells washed with fresh medium, and 200 [micro]l of fresh medium were then added. The plates were incubated at 37 [degrees]C for a recovery period of 6 days and cell growth was then analysed using the SRB assay. Three replicates were used to determine the cytotoxicity of each extract.

Sulphordamine B (SRB) assay (Skehan et al. 1990)

This colorimetric assay was performed to assess growth. It estimates cell numbers indirectly by staining total cellular protein with SRB (Skehan et al. 1990). In brief, cells were fixed by layering 100 [micro]l of ice-cold 40% trichloroacetic acid (TCA) (Merck) on top of the growth medium and incubated at 4[degrees]C for 1 h. Plates were then washed five times with cold water. The excess water was then decanted and the piates left to dry in air. SRB stain (50 [micro]1; 0.4% in 1% acetic acid) (Sigma) was added to each well and left in contact with the cells for 30 min. The cells were then washed with 1 % acetic acid, rinsed 4 times until only the dye adhering to the cells was left. The plates were then air-dried and 100 ([micro]1 of 10 mM Tris base pH 10.5(Sigma-Aldrich) were added to each well to solubilise the dye. The plates were gently shaken for 20 min on a gyratory shaker and the absorbance (OD) of each well was read on a SLT 340 ATTC plate reader (SLT Lab instrument, Australia) at 492 nm. Cell survival was measured as the percentage absorbance compared to the absorbance of a control (non-treated cells). The [IC.sub.50] values were calculated using the Anilisa[R][R] program by plotting the percentage survival versus the concentrations, interpolated by cubic spine. According to the National Cancer Institute guidelines (Boyd 1997), extracts with [IC.sub.50] values < 20 [micro]g/ml were considered to be active.

Results and discussion

The initial cytotoxicity testing of the dichloromethane crude extract against the COR-L23 cell line clearly demonstrated strong activity ([IC.sub.50] value 2.53 [micro]g/ml). Subsequent fractionation of the crude extract revealed that this activity was not due to any unique new compounds in G. undulatus, but to known acetogenins and styryilactones.

This phytochemical study of G. undulatus root extracts led to the isolation of three known styryl lactones (Fig. 1), including 5-acetoxyisogoniothalamin oxide (1), O-acetylaltholactone (2) and altholactone (3) and four known acetogenins (Fig. 2) including annonacin (4), cis-annonacin (5), goniothalamicin (6) and cis-goniothalamicin (7). The chemical structures of all compounds were determined by spectroscopic analyses, and the data were in agreement with those published previously. The placement of the tetrahydrofuran ring in acetogenin was determined by analysis of the mass fragmentation pattern. The relative stereochemistries of the furan rings and adjacent chiral centers were determined by comparison of the (1) H NMR data with known synthesized analogues (Fujimoto et al. 1994].

[FIGURE 1 OMITTED]

Results from the analysis of the cytotoxic activity by using the SRB assay against large cell lung carcinoma (COR-L23) and human fetal fibroblast normal cell lines (MRC-5) are shown in Table 1. These results indicated that all isolated compounds showed cytotoxic activity against COR-L23, with the isolated acetogenins (compounds 4-7 showing higher cytotoxic activity ([IC.sub.50] values in range of 0.54-1.71 [micro]M) than the styryl lactones (compounds 1-3)([IC.sub.50] values in the range of 7.37-15.43 [micro]M).The annonaceous acetogenins also had higher cytotoxic activity against the normal cell line than the styryl lactones, with [IC.sub.50] values in the range of 11.82-31.44 [micro]M and 48.67-102.82 [micro]M, respectively. Among the seven compounds, only annonacin exhibited a selective index value ([IC.sub.50] MRC-5/[IC.sub.50] COR-L23) of 27.8, that was close to the selective index of vincristine ([IC.sub.50] MRC-5/[IC.sub.50] cor-L23 =29.3).
Table 1

Cytotoxic activity of isolated compounds from G. undulatus root
extracts.

Compounds                  [IC.sub.50]([micro]M) [+
                          or -] S.E.M.
                          [IC.sub.50]
                          ([mu]g/ml)]

                          COR-L23

Styryl lactones

5-Acetoxyisogoniothalamin  7.37 [+ or -] 0.20(2.02
oxide (1)                  [+ or -] 0.05)

O-Acetylaltholactone (2)   11.44 [+ or -] 0.22
                          (3.13 [+ or -] 0.06)

Altholactone (3)           15.43 [+ or -]
                          0.47(3.58[+ or -]0.11)

Annonaceous acetogenins

Annonacin (4)              0.56 [+ or -] 0.02
                          (0.34 [+ or -] 0.01)

cis-Annonacin (5)          0.54 [+ or -]
                          0.00(0.32[+ or -]0.00)

Coniothalamicin (6)        1.68 [+ or -] 0.09(1.00
                          [+ or -] 0.05)

cis-Goniothalamicin (7)    1.71 [+ or -] 0.27(1.02
                          [+ or -] 0.16]

Vincristine                0.12 [+ or -] 0.00(0.11
                          [+ or -] 0.00)

Compounds                                          Selective
                                                  Index

                          MRC-5

Styryl lactones

5-Acetoxyisogoniothalamin  48.67 [+ or -]                6.6
oxide (1)                  0.20(13.34 [+ or -]
                          0.06)

O-Acetylaltholactone (2)   92.34 [+ or -] 0.02           8.1
                          (25.30 [+ or -] 0.00)

Altholactone (3)           102.82 [+ or -]               6.7
                          0.92(23.85[+ or
                          -]0.21)

Annonaceous acetogenins

Annonacin (4)              15.62 [+ or -]               27.9
                          0.26(9.31[+ or -]0.15)

cis-Annonacin (5)          11.82 [+ or -]               21.9
                          0.15(7.04 [+ or -]
                          0.09)

Coniothalamicin (6)        18.38 [+ or -] 0.02          10.9
                          (10.95 [+ or -] 0.01)

cis-Goniothalamicin (7)    31.44 [+ or -] 0.08          18.4
                          (18.74 [+ or -] 0.05)

Vincristine                3.51 [+ or -] 0.21           29.3
                          (3.24 [+ or -] 0.19)


The mode of action of acetogenins as anticancer agents mainly targets the mitochondrial NADH-ubiquinone oxidoreductase, also known as respiratory complex I of mitochondria. This complex I transfers electrons from NADH to ubiquinone and links this process with the translocation of protons across the membrane to generate an electrochemical gradient that drives the ATP synthesis (Tormo et al. 1999). The study on the biological effect of annonacin on cancer cell lines established that annonacin activiated p21 and arrested cancer cells at a growth-static G1 phase. Furthermore, it caused more significant cytotoxicity to cancer cells in the growth period (S phase) (Yuan et al. 2003). To explore new lead compounds as anticancer agents has led to modifications of acetogenins including, a multi-ether mimic (Liu and Yao 2005), of their lactam analogues (Liu et al. 2007), and nitrogen-containing heterocyclic analogues (Kojiyama et al. 2008). These modifications led to the discovery of more selective analogues such as a 1 -methylpyrazol-5-yl derivative of solamin. However acetogenins from natural sources could be good precursor molecules. Because the acetogenins from Annonaceae posses a terminal [alpha],[beta]-unsaturated [gamma]-lactone ring, this could be a pharmacophore to react with new putative target proteins (Derbre et al. 2008). Thus the continuing phytochemi-cal investigation of Goniothalamus in Thailand cannot only identify new lead compounds as anticancer agents but also provide a pool of chemicals for future biological target studies.

[FIGURE 2 OMITTED]

Acknowledgements

We thank Asst. Prof. Dr. Choathip Purintavaragul, Department of Biology, Faculty of Sciences, Prince of Songkla University, for her help in the identification of the plant and Miss Srisopa Rueng-noo, Applied Thai Traditional Medicine Centre, Faculty of Medicine, Thammasart University, for her kindness in assistance with the cytotoxic assay. We would like to thank the Graduate School, Prince of Songkla University and the Academic Excellence Enhancing Program in Pharmaceutical Science, Prince of Songkla for research funding and Prof. LA. Damani for his scientific suggestion.

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S. Tantithanaporn (a), C. Wattanapiromsakul (a), * A. Itharat (b), N. Keawpradub (a)

(a) Department of Pharmacognosy and Pharmaceutical Botany, Faculty of pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112. Thailand

(b) Applied Thai Traditional Medicine Centre, Faculty of Medicine, Thammasat University, Rungsit Campus, Klongluang, Patumthani 12121, Thailand

* Corresponding author. Tel: +66 74 428220; fax: +66 74 428220. E-mail address: chatchai.w@psu.ac.th (C Wattanapiromsakul).

0944-7113/$ - see front matter [C] 2010 Elsevier GmbH. All rights reserved.

doi: 10.1016/j.phymed.2010.10.010
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Author:Tantithanaporn, S.; Wattanapiromsakul, C.; Itharat, A.; Keawpradub, N.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9THAI
Date:Apr 15, 2011
Words:4282
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