INTRODUCTION:

Cancer is the second-highest cause of mortality and a public health issue worldwide.^1-2Cancer is abnormal cell growth that is uncontrolled and can cause metathesis in other tissues.³ One of the most frequently diagnosed cancers in women is breast cancer, where around 1.67 cases occur each year.³

Several Garcinia species have potential as anticancer agents; for example, Garcinia atroviridis has activity against Hella cell line cancer (cervical cancer), human lung cancer cells (H-40), human breast adenocarcinoma cell line (MCF-7), and human prostate cancer cell line (DU-145).⁴

G. cantleyana has activity against HeLa cancer cells, ovarian cancer cells (CaOV-3), breast cancer cells (MDA-MB-2310, MCF-7), and activity against cells (NCI-H460) as well as cells (Du-145).^5-6

The use of antioxidants as cancer chemopreventive agents has been demonstrated by free radical research to be crucial in preventing the diseases.^7-9 Antioxidant and anticancer activity of compounds and extracts of Garcinia mangostana were reviewed by Ansori et al. (2020)¹⁰, Mahmudah et al. (2021)¹¹ and Vien et al. (2021).¹² Antioxidant activities also reported from G. pedunculata¹³, G. hanburyi¹⁴, and G. prainiana.¹⁵

The phytochemical content of G. maingayi that has been reported contains xanthone, 1, 3, 7-trihydroxy-2- (3-methyl but-2-enyl), xanthones, benzophenones, isoxantones chemicals, triterpenoids, stigmasterol, and sitosterol.¹⁶ Acetone is extracted from G. maingayi twigs have also been reported. It was successfully isolated with the obtained phytochemical compounds, such as griffipavixanthone, isoxanthoxymol, 5,7,2',5' tetrahydroxyflvaa-3-ol, and kamboginol.¹⁷ The methanol extract of G. maingayi stems demonstrated the most selective activity against MCF-7 cells (IC₅₀ 3-8µg/mL) as well as the highest cytotoxicity.¹⁸ Several studies related to phytochemical compounds from garcinia species that were tested on human leukemia cancer cells have been reported, including compounds such as xanthochymol, isogarcinol, and benzophenone garcinol derivatives.¹⁹ The compound 7-Epiclusianone, which was isolated from G. brasiliensis, has shown potential against glioblastoma cells.²⁰ In addition, α-mangostin and cowanin, which were isolated from methanol extract of G. cowa, have demonstrated potential in fighting the MCF-7 cell line.²¹ The isolation of Oblongifoline C, a compound produced by G. yunnanensis, has been shown to inhibit esophageal cancer in vitro and in vivo and to inhibit pancreatic cancer cells. Guttiferon K and Oblongifoline C compounds also have activity in inhibiting human colorectal cancer cells.^22-26

Garcinol and other phytochemical compounds such as isophrenyl benzophenone, guttiferones K, M, and I, and oxyguttiferones K, K2, and M has been isolated G. cambogia extract and shown to be active as a topoisomerase II inhibitor. C. cambogia extracts also showed anticancer against Colon Adenocarcinoma (Caco-2) Cell Line.²⁷ Another gamboge compound from G. maingayi is reported to be able to eliminate stasis, has the effect of splitting blood, stops bleeding, and is detoxifying; it is used to treat various diseases, including cancer and encephaledema.²⁸ It has also been reported that garcinol from the Garcinia species is also active as an antiplatelet aggregator.²⁹ The results of other studies showed the anti-inflammatory effect of gambogic acid obtained from G. maingayi.³⁰ Traditionally, G. maingayi leaves are used as antipyretic drugs.¹⁸

A preliminary investigation was conducted to evaluate the anti-cancer and antioxidant activities of the stem bark n-hexane extract from G. maingayi. This extract's anti-cancer and antioxidant activities were 96.87% inhibition for an extract concentration of 200µg/mL and 90.51% inhibition for an extract concentration of 100 µg/mL, respectively. This study aims to identify pure compounds that can be isolated from the hexane extract of G. maingayi stem bark. The compounds contained in this extract are predicted to have a significant correlation with the antioxidant and anticancer activities of MCF-7. This research is also supported by data on the interaction of pure compounds with cancer cell receptors through molecular docking.

MATERIALS AND METHODS:

Plant Collection:

The stem bark of G. maingayi H was taken from a plant collection in the Riau archipelago, Indonesia. This plant species was identified by Dr. Ismail, and his specimens are kept at the Herbarium Bogoriense National Research and Innovation Agency (BRIN).

Instrumentation:

UV-Vis measurements using the Cary 60 Agilent Technologies spectrophotometer. Melting point measurement using Fisher Scientific apparatus. IR spectra were measured using a Shimadzu FTIR Prestige-21 diode array spectrophotometer.¹H-NMR and ¹³C-NMR were measured using JEOL-ECS 400 MHz NMR spectroscopy. The molecular weight of the compounds was measured using the QTOF LC-MSMS. Thin-layer chromatography using silica gel GF254 (E. Merck). Purification using column chromatography using silica gel GF254 (E. Merck) with a gradient system of hexane, ethyl acetate, and methanol. Sephadex LH-20 eluted with methanol: CH₂Cl₂(1:1).

Extraction and Isolation:

The bark powder was dried in an oven at 50^oC. A total of 1.57kg of dry bark powder was extracted in stages, first using n-hexane (4 x 5L). The solvent was evaporated, and then 44.07g of hexane extract was obtained. Furthermore, the above samples were extracted again using acetone (4 x 5L) and, after the acetone solvent was evaporated, 128g of acetone extract was obtained. 18g of the hexane extract was fractionated using a silica gel chromatography column with 50g of silica gel. The extracts were eluted with n-hexane and ethyl acetate with a gradient (1:0 to 0:1v/v) as the mobile phase. Separation by this column chromatography produces two compounds: stigmasterol and kamboginol. The acetone extract, as much as 80 g, produces three compounds: isoxantochymol, griffin pavikxanthone, and 5, 7, 2', 5'-tetrahydroxy flavan-3-ol, which has been reported.²¹ Furthermore, 20g of hexane extract was purified using a 275-g silica gel chromatography column. The column was eluted with n-hexane and ethyl acetate with increasing polarity (1:0 - 1:1 v/v) to give six fractions (1A–6F). This fraction was re-evaluated by thin-layer chromatography. The 5E fraction (2.18g) was then subjected to another 48g of silica gel chromatography and eluted with n-hexane:ethyl acetate (9:1) to produce the garcinol compound.

Antioxidant assay:

The evaluation of antioxidant activity was performed by assesing the free radical scavenging activity using the DPPH (1,1-diphenyl-2-picrylhydrazyl) method.³² This test using DPPH has an absorption at a maximum wavelength of 520nm in the form of a dark purple color, which will disappear when reduced by radical compounds. Garcinol in methanol at a concentration of 0-100µg/mL in 2.5mL was mixed with DPPH (0.5mM in MeOH) in as much as 500µL. Furthermore, the samples were incubated at room temperature for 30 minutes. The ability of antioxidant activity to protect cells is calculated using the following equation:

A0- A1

% Inhibition = ----------- X 100

The absorbance of the control reaction was denoted as A0, while A1 was used to represent the absorbance in the presence of the sample. In measuring this antioxidant activity, its activity is calculated as IC₅₀, where the IC₅₀ value is the value for scavenging 50% of DPPH radicals. The antioxidant activity was tested using the quercetin compound as a positive control.

Anticancer assay:

In this study, the MCF-7 breast cancer cell line was used to assay the activity of cancer cells. The anticancer activity was evaluated in RPMI-60 medium (GIBCO) supplemented with 10% v/v Fetal Bovine Serum (Sigma) and 1% antibiotic-antimycotic (GIBCO). The cells and medium were incubated at 37^oC with 5% CO₂. A cell suspension (5x104 cells/mL) was added to each well of a 96 well microplate for the cancer sell assay. The cell were then incubated at 37^oC under 5% CO₂ for 24hours before being treated with various concentrations of garcinol (0-30μg/mL) and incubated for another 24 hours. Afterward, 0.5mg/mL MTT (Sigma) was added to the cells and incubated for 4hours. The MTT reaction was stopped with DMSO and incubated for 10-15 minutes. Cell viability was measured with a microplate reader at a maximum wavelength of 550nm, and the calculation of cell viability was determined uding the following equation:

OD sample – OD media

% Cells viability = ---------------------------------------- × 100 %

OD cell – OD media

IC₅₀ was taken as concentration that caused 50 % inhibiton of the cell viability.

Molecular Docking Study:

The garcinol's 2D chemical structure was drawn in Chem Draw version 12.0 and converted to 3D format. AutoDock 4.2 and Discovery Studio Visualizer 4.0 were used for molecular docking analysis and visualization. 3ERT receptors, which are -estrogen receptors obtained by downloading from the Protein Data Bank, were used in this molecular docking study. These receptors and their native ligands were subjected to external validation by re-docking the native ligands and the 3ERT receptor. The center of a grid box was placed on the binding site where the ligand had crystallized. The coordinates of the box were specified as 22.438, 8.003, and 113.539 for the x, y, and z axes, respectively. To asses the efficacy of the molecular docking- technique, the native ligand was redocked onto the target protein, which had its original ligand removed, udsing AutoDock 4.2 software and RMSD parameter.

RESULT:

Isolation of garcinol compounds:

The compound isolated from the stem bark of G. maingayii Hook by n-hexane fractionation was 10.2mg of the pale yellow powder. The compound obtained is a pure compound because, from the TLC profile, only one spot is visible. The melting point this compound is 122-124^oC.^33-34

FTIR:

The FTIR spectrum is characterized by prominent peaks at 3564-3274 cm^-1for hydroxyl groups, as well as at 1728 cm^-1for unconjugated carbonyl groups and 1623 cm^-1for conjugated carbonyl groups.

Figure 1: IR spectroscopy of Garcinol

Mass Spectroscopy:

The results of the LC/ESI-MS-MS analysis of garcinol compound showed a single peak at a retention time (tR) of 8.15 minutes.

Figure 2: Mass spectroscopy of Garcinol

The correlation between the ¹³C-NMR data of C-22 to C-23 and C-4, C-5 and C-6 was determined using HMBC. Based on the analysis, the yellow powder sample was identified as a garcinol compound.

Figure 5: Chemical structure of Garcinol

Table 1: Chemical shift ¹H NMR and ¹³C NMR of Garcinol

Position	δ_H (ppm),multiplicity, J (Hz)	δ_C(ppm)
1		194.0
2		116.0
3		195.0
4		69.9
5		49.8
6	1.39 (1H, m)	46.9
7	1.87 (1H, dd, 14.4; 3.6)	42.7
	2.57 (1H, d, 14.0)
8		58.0
9		209.3
10		199.1
11		128.0
12	6.90 (1H, d, 1.6)	114.5
13		143.6
14		149.8
15	6.58 (1H, d, 8.4)	116.6
16		120.3
17		26.6
18		122.8
19		135.4
20	1.57 (3H, s)	26.3
21	1.68 (3H, s)	18.4
22	1.14 (3H, s)	22.9
23	0.99 (3H, s)	27.2
24	2.05 (2H, m)	29.0
25	4.91 (1H, t, 6)	123.9
26		133.1
27	1.64 (3H, s)	25.9
28	1.53 (3H, s)	18.1
29	2.11 (1H, d, 3.4) 2.15 (1H, d, 10.1)	36.3
30	1.97 (1H, m)	43.7
31		148.2
32	4.37 (2H, d, 18.4)	112.9
33	1.72 (3H, s)	17.8
34	2.08 (2H, m)	32.7
35	5.01 (1H, t, 6)	124.3
36		132.2
37	1.78 (3H, s)	26.0
38	1.51 (3H, s)	18.1

In vitro assays of antioxidant and anticancer activities of Garcinol

Table 2: Garcinol bioactivities

Bioactivities

IC₅₀ μg/mL

Antioxidant

(DPPH free radical scavenging activity)

16.44±0.015

Anticancer

(in vitro against MCF7 breast cancer cells

19.13±0.013

Molecular Modeling Studies:

Figure 6: Interaction of Garcinol binding with α-estrogen receptor ERT

DISCUSSION:

The FTIR spectrum analysis of garcinol compound shows a sharp absorption with weak intensity at wave number 3,564 cm^-1 and a broad absorption at 3,274 cm^-1 indicating the presence of OH group which is strengthened by the presence of C-O group in the region of 1,298 cm^-1. Meanwhile, the absorption at wave numbers 2,969 cm^-1 and 2,872 cm^-1 indicates the stretching vibrations of methyl group (CH₃). The stretching vibration at wave number 2,923 cm^-1 indicates the presence of aromatic C-H groups which is supported by the stretching vibration of C=C in the region of 1,529 cm^-1. The stretching vibration of the methyl group (-CH₃) is shown in the region of 2,969 cm^-1 which is strengthened by the presence of C-H bending vibration at 1,435 cm^-1. Based on the FTIR spectrum analysis, it is indicated that garcinol compound contains aromatic group, OH group, and carbonyl group (C=O). The presence of –OH and conjugated –C=C- aromatic groups in this aromatic ring indicate a potential group as antioxidant agent (Bors et al., 1990).

The mass spectrum of the garcinol compound shows the molecular ions [M+Na]⁺ and [M+H]⁺ of the garcinol compound respectively at m/z 625.3 and 603.3, which means that the molecular weight of the garcinol compound that is 602.3. The molecular weight corresponds to the molecular formula C₃₈H₅₀O₆ and is indicated as a benzophenone group compound.

The ¹H-NMR spectrum shows the presence of a broad singlet peak (bs) seen at a shift of δH 6.51 and 6.82 which indicates the presence of 2 –OH groups (1H, bs) attached to an aromatic ring. Protons in the phenolic group are usually present in the broad singlet form in the δH range of 6-8ppm (Supratman, 2010). Meanwhile, the presence of a typical aromatic ring with 3 proton signals is seen at a chemical shift (δH) of 6.58; 6.90; 6.94 ppm. Proton doublet (dd) signal at δH 6.94 (1H, dd, 8.4; J= 1.6 Hz) indicates an ortho-proton match at δH 6.58 (1H, d, J= 8.4 Hz) as well as meta-matching with a proton δH 6.90 (1H, d, J= 1.6 Hz). Proton signals in the H-NMR spectrum also indicate the presence of 9 methyl groups. The proton peak of the 2 methyl groups on the saturated carbon (–CC=CH– CH₂–), which makes up the isoprenyl framework attached to the aromatic ring, is shown by the triplet peak at the δH shift of 4.91; 5.01; 5.08. At a shift of δH 4.37, a proton duplet signal appears (2H, d) indicating the presence of a methylene group on the unsaturated carbon –CH₂=C–CH₃, which is also a proton from the isoprenyl framework.

The ¹³C NMR analysis data showed the carbon signals of the garcinol compound. This compound exhibits the presence of two aromatic rings as well as a carbonyl carbon (C=O). The first aromatic ring signal is a phenolic group (6 carbon atoms bonded to an OH group) consisting of 3 aromatic carbons (C aromatic), 2 phenolic carbons (Aryl-C-OH), and 1 carbon bonded to a carbonyl (Aryl-C-C =O) indicated by the chemical shift ( δ C) respectively 114.5; 116.6; 120.3; 143.6; 149.8; 128.0. On chemical shift (δC) 194.0; 116.0; 195.0; 69.9; 58.0; 209.3 respectively indicates the presence of another aromatic ring of 6 carbon atoms, consisting of 1 vinylic carbon bonded to the -OH group (=CH-OH), 1 vinylic carbon (=CO), 1 conjugated ketone carbon (-C=O), 2 quaternary carbons in the cyclic ring, and 1 ketone carbon (-C=O) in the cyclic ring. Meanwhile, the presence of a carbonyl bridge connecting the two aromatic rings is indicated by the conjugated ketone group (-C=O) at a chemical shift (δC) of 199.1ppm.

Results of the antioxidant and in vitro anticancer activities of garcinol indicates that garcinol has good performance for both activities. Although the IC₅₀ to scavenge DPPH of garcinol is higher than that of the positive control, quercetin, A compound with an IC₅₀ greater than 20µg/mL is still considered a very active antioxidant compound, according to Molyneux (2004).³⁰ The results of this study were in accordance with a study reported by Yamaguchi et al (2000) which also suggested that garcinol had good DPPH scavenging activity.³³ This good antioxidant activity might be due to the many hydroxyl (-OH) groups in garcinol, as described by Cai et al (2006), where the more –OH present in the compound, the more H can be donated to scavenge the DPPH.³⁴ The results of testing the antioxidant activity with the DPPH method showed that garcinol showed strong radical-scavenging activity. This activity is almost three times higher than the activity of tocopherol. And this garcinol activity is equivalent to 85 % of ascorbic acid activity. The reaction rate of this activity has been reported by Krishnamurthy and Yamaguchi.^31,33 While in testing, the activity of garcinol can inhibit MCF-7 cancer cells. Garcinol in MCF-7 cells and xenograft models activates ASK1-activated mitogen protein kinase and also stress activation protein kinase (SAPK).³⁵ In MCF-7 breast cancer cells, estradiol works by inhibiting apoptosis and stimulating cell proliferation. The presence of garcinol compounds can inhibit estradiol induced cell proliferation and induce apoptosis. The possible mechanism involves decrease acetate levels and as pathway leading to theo downregulation of cyclins.³⁶ Garcinol's mechanism of action in modulating anti-cancer effects has been reported by Aggarwal et al., 2020, through the use of regulating various cellular processes.³⁷

Estrogen is the main female sex hormone, in this mammary tissue estrogen plays an important role in the female reproductive organs such as the ovaries and mammary tissue. This hormone is often a trigger for cell growth in breast cancer. There are two types of ER that are expressed in mammalian cells namely α-ER and β-ER. α-ER is responsible for the regulation and enhancement of DNA transcription so that it has an important role in regulating breast development when compared to β-ER.³⁸ The hormones estrogen and progesterone play important roles in female reproduction. To find out if a woman has breast cancer, like it or not, she needs to test for cancer cells by removing the cancer cells through a biopsy. This biopsy is to identify cancer cells and whether they contain estrogen or progesterone receptors. Breast cancer cells that have estrogen receptors are generally referred to as "ER+." One example of these cells is MCF-7. Many studies related to breast cancer cells use MCF-7 cells as a model for breast cancer cells. MCF-7 cells have characteristics such as resistance to chemotherapy agents, expression of estrogen receptors (ER+), overexpression of Bel-2, and lack of Caspase-3 expression.³⁹ To assess anticancer activity in silico, we used molecular docking to look at the interaction between garcinol and the α-estrogen receptor ERT. The interaction between amino acid residues on the α-estrogen receptor with an energy value of -6.24 Kcal/mol and an inhibition constant of 26.7µM was observed in the results of garcinol binding to the α-estrogen receptor. Garcinol has the potential to inhibit cancer via the α-estrogen receptor based on its energy value and inhibition constant.

CONCLUSION:

The garcinol compound, identified by the molecular ion at [M+H]⁺ =603.3710, melting point of 133-135^oC, molecular formula C₃₈H₅₀O₆, and corresponding H-NMR and C-NMR, was found to be the active com;pound in the hexane fraction isolated from Garcinia maingayi Hook, in the form of a yellow powder. Garcinol demonstrated antioxidant activity and breast cancer (MCF-7) activity at concentrations of 16.44 µg/mL and 19.33µg/mL, respectively. These findings suggest that garcinol, with a binding energy of -6.24 kcal/mol and an inhibition constant of 26.7µM, plays an important role in the interaction with human -estrogen receptors.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest regarding the publication of this article. Authors confirmed that the data and the paper are free of plagiarism.

ACKNOWLEDGMENTS:

We would like to express our gratitude to Mr. Ismail and the Research Center for Biology (BRIN) staff for their assistance in collecting and analyzing the specimens. All the authors contributed equally to this work as main contributors.

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Received on 04.04.2023 Modified on 22.12.2023

Research J. Pharm. and Tech 2024; 17(8):3546-3552.

DOI: 10.52711/0974-360X.2024.00554