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ORIGINAL ARTICLE
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Anticancer, anti-proliferative activity of Avicennia marina plant extracts


1 Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
2 Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia

Date of Submission27-Aug-2019
Date of Decision01-Nov-2019
Date of Acceptance30-Dec-2019
Date of Web Publication19-Oct-2020

Correspondence Address:
Kamel A Saleh,
Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_659_19

 > Abstract 


Purpose: Medical halophytes plants are potent sources of bioactive secondary metabolite components used against different diseases. Avicenniamarina one of the typical halophytes plant species used in folk medicine to treat smallpox, rheumatism, and ulcer. Despite the richness of A.marina with polyphenolic, flavonoids, terpenoid, and terpene, contents remain poorly investigated against cancer types. Consequently, to explore the function-composition relationship of A.marina hexane leaves crude extract, the current study designed to investigate the cytotoxicity, apoptotic and antiproliferative impacts on the colon (HCT-116), liver (HepG2), and breast (MCF-7) cancer cell lines.
Materials and Methods: Therefore, the cytotoxicity impact screening carried out by Sulforhodamine-B assay. While, the initiation of the apoptosis evaluated by chromatin condensing, early apoptosis, late apoptosis and the formation and appearance of apoptotic bodies. On the other hand, the flow cytometry used to identify the phase of inhibition where the determined IC50 value used. While, the chemical composition of the hexane extract was detected using liquid chromatography-mass spectrometry/mass spectrometry.
Results: Revealed that hexane extract showed a weak induction of apoptosis despite the formation of apoptotic bodies and the high cell inhibitory effect on all tested cell lines with IC50 values (23.7 ± 0.7, 44.9 ± 0.93, 79.55 ± 0.57) μg/ml on HCT-116, HepG2, and MCF-7, respectively. Furthermore, it showed the ability to inhibit cell cycle in G0/G1 for HCT-116, S phase for HepG2, and MCF-7.
Conclusion: In the light of these results, the current study suggests that A.marina leaves hexane extract may be considered as a candidate for further anticancer drug development investigations.

Keywords: Acanthaceae, Avicennia marina, HCT-116, HepG2, hymecromone, MCF7



How to cite this URL:
Albinhassan TH, Saleh KA, Barhoumi Z, Alshehri MA, Al-Ghazzawi1 AM. Anticancer, anti-proliferative activity of Avicennia marina plant extracts. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298618




 > Introduction Top


Cancer is a word pointing to a cell or a group of cells that have lost the control of the cell cycle by avoiding the checkpoint [1],[2] leading to rapid and continuous proliferation. Subsequently, cancer cells gain characteristics enabling them to invade and metastasize to other tissues leading to the formation of new cancer foci and colony in different organs of the body.[3],[4],[5] The attempts to understand the mechanisms leading to cancer are almost ambiguous. While endeavours have achieved many advances by developing new anticancer agents, curing cancer or controlling the progression of the disease remains a difficult goal to be reached.[6],[7],[8],[9]

Nature, which considered as the primary source of many medicines has provided pharmacy with different anticancer drugs.[10],[11],[12] In contrast, plants are one of the primary sources of a natural product with pharmacological impacts. However, there is a disparity between plants of the same species regarding their medicinal chemical constituents.[13] This content is often changed depending on the environmental conditions surrounding these plants.

Halophytes plants can grow naturally in diverse environments including those with harsh conditions such as salinity and drought. Not surprising, under such conditions various physiological and biochemical mechanisms responsible for regulating growth and development, are developed to ensure the survival of the plant.[14],[15],[16] These mechanisms may explain why Halophytes plant can found in, salt lakes, dunes, inland deserts, coastal salt marshes, and muddy seashores. Such environmental stress conditions are demonstrated to be a direct inducer of high activity of antioxidant mechanisms in different plants.[17],[18] Consequently, it is straightforward to expect that halophytes grown under stress would produce antioxidants more than other plants.[18] Different studies showed that halophyte extracts chemical constituents are rich in bioactive compounds (primary and secondary metabolites) such as essential oils, polysaccharides, carotenoids, polyunsaturated fatty acids, vitamins, sterols, terpenes and glycosides.[19],[20],[21],[22] Halophyte extracts are also rich in phenolic compounds which exhibit several biological activities, including anticancer, antioxidant, antifungal, antimicrobial, and anti-inflammatory activities.[23],[24],[25],[26]

Avicenniamarina is a member of the halophyte plants family contains primary and secondary metabolites like polyphenol which has been reported to induce apoptosis in human breast and liver cancer cells.[27] Momtazi-Borojeni et al.[28] reported that A.marina crude extract induces apoptosis in MDA-MB 231 breast cancer cells invitro. While A.marina- derived component named Isoquercitrin exhibits weak induction of apoptosis in the cervical cancer cell line SiHa,[29] another isolated compound naphtha (1,2-b) furan-4,5-dione (NFD) has shown significant induction of apoptosis in human MDA-MB 231 breast cancer cells.[30] Furthermore, Furano-1,2-naphthoquinone has been showing potential antitumor activity against different cancer line including HepG2 liver cancer cells.[31],[32]

Apoptosis considered as the merciful and the favorite pathway to remove cancer cells because the process of apoptosis is known to induce immune system responses to phagocyte and engulf apoptotic cancer cells.[33],[34]

The current study aimed to evaluate the potential antiproliferative and apoptotic induction of non-polar component of A.marina plant which grown under high-stress conditions “high salted land and high temperature (35°C–45°C) climate” in Asser region beach in the kingdom of Saudi Arabia. Whereas, all signs pointed that under such stress conditions, the plant A.marina contains potentially impacted metabolites that may have the ability to initiate different molecular mechanisms inside different cancer cell lines.


 > Materials and Methods Top


Cell lines, chemicals, and biochemicals

Ethanol, methanol, and Sulforhodamine B (SRB) stain purchased from Sigma Chemical Co.(St. Louis, MO, USA). All other chemicals obtained from Gibco/Life Technologies Co, (Carlsbad, CA, USA) unless mentioned otherwise. While cell culture vessels usually replenished from Nunc Co.(Roskilde, Denmark). Human colon (HCT 116), Human liver (HepG-2) and Human breast (MCF-7) cancer cell lines acquired from Vacsera (Giza, Egypt). Cells routinely maintained in RPMI 1640 cell culture media supplemented with 1 mM sodium pyruvate, 2 mM L. glutamine, 100 units/ml penicillin-streptomycin and 10% fetal bovine serum. Subsequently, they incubated in a humidified, 5% CO2 supplemented atmosphere at 37°C.

Plant collection and crude extract preparation

The fresh leaves of A.marina, Acanthaceae, collected from Alberk beach at (18.335097,41.461967), Asser region, The kingdom of Saudi Arabia on 21 July 2017. For the crude extract preparation, 900 g of fresh leaves washed with distilled water then immersed with 2 L of aqueous ethanol 80%, left for 7 days with stirring at room temperature (18°C–24°C). The ethanol extract was filtered using filter paper and concentrated to dryness under reduced pressure using a rotary evaporator at 40°C (Ikia-Germany). The concentrated crude extract weight 110 g and the extraction yield 12%. The crude extract then fractionated between distilled water and hexane to get the non-polar component of the plat. Dried Fraction extracts then obtained by using rotary evaporator at 40°C followed by incubation at room temperature (20°C–26°C) for five days. The hexane crud extract weighted 0.793 g and the extraction yield 0.72% from the ethanol yield. The dried extracts were stored at 4°C until required.

Profiling of compounds by liquid chromatography-mass spectrometry/mass spectrometry

Analyses were performed on SCIEX X500R QTOF system includes ultra-performanceliquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) (Woodlands Central Indus. Estate. SINGAPORE). The separation was performed using Phenomenex Kinetex 2.6 μm Phenyl-Hexyl 100 A (50 mm × 4.6 mm). The mobile phase consists of, Phase A (10 mM ammonium format in water) and Phase B (0.05% formic acid in methanol). A variable gradient flow rate was used, which is described in [Table 1]. A Positive Non-targeted mode was used for the analytes.
Table 1: Gradient flow rate

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Drug dose preparation

0.01 g of hexane extract diluted in 1 ml of dimethyl sulfoxide as a stock solution.

Cytotoxicity measurement of Avicennia marina extracts

The cytotoxicity and anticancer activities of prepared A.marina leave crude extracts were tested against human breast (MCF-7), human colon (HCT 116), and human liver (HepG-2) cancer cell lines using SRB assay described by Skehan et al.[35] Different cancer cell lines exposed to a range of concentrations (0.01–100 μg/ml) of hexane, ethyl acetate, and n-butanol crude extracts then incubated in 5% CO2 humidified incubator at 37°C for 72 h. Doxorubicin used as a positive control. Treated cells (TC) were fixed with TCA (10%) for 1 h at 4°C. Subsequently, to remove TCA, cells were washed with water many times, and then 0.4% SRB solution was used to stain cells in a dark place for 10 min. Stained cells washed with 1% glacial acetic acid. Finally, to dissolve SRB-stained cells, 10 mM Tris–HCl (pH 10.5) was used. After drying overnight, the color intensity of remained cells was measured at 540 nm by ELISA (Anthos, zenith 200 rt, Biochrom LTD, Cambrage, England).

Detection activity signals of apoptosis

For apoptotic bodies detection TC were washed using phosphate-buffered (PBS) washing buffer twice and then collected using 0.25% trypsin–EDTA and transferred to staining slide. Cells were stained using 100 μg/ml Ethidium bromide (EtB) and 100 μg/ml Acridine Orange 1 v: 1 v Stained apoptotic bodies were detected and photographed under Nikon Fluorescent microscope Japan.[36]

Cell cycle distribution using DNA flow-cytometry

Adherent cancer cells exposed to IC50 equivalent concentrations of extract solutions for 48 h. Cells were then suspended using 0.25% trypsin-EDTA, washed with ice-cold PBS, and re-suspended in 0.5 ml of PBS. Cells were then fixed in 70% ice-cold ethanol at 4°C for 1 h before transferred to −20°C until required for analysis. Upon analysis, fixed cells were washed with ice-cold PBS and re-suspended in 1 ml of PBS containing 50 μg/ml RNase A and 10 μg/ml propidium iodide. After 20 min incubation at 37°C, cells were analyzed for DNA contents by FACSVantageTM (Becton Dickinson Immunocytometry Systems, San Jose, CA). For each sample, 10,000 events were acquired. Cell cycle distribution was calculated using CELLQuest software (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA).[37]

Statistical analysis

The optimum IC50 calculation was performed using Sigma Plot version 12.0 (Systat Software Inc, Chicago, USA).


 > Results Top


Cytotoxicity

The evaluation of the cytotoxic impact by “SRB assay”[23] of A.marina hexane extract against three different cancer cell lines; Human Colon “HCT-116,” Human Breast “MCF-7,” and Human Liver “HepG2” cancer cell lines, revealed that hexane extract presents significant cytotoxic activities with potential selectivity against tested colon cancer cells comparing to other cancer types used in the current study [Table 1] and [Figure 1]. Interestingly, while the highest antiproliferative cytotoxic activities of hexane extract detected against HCT-116 colon cancer cells (IC50 23.7 ± 0.74 μg/ml), the cytotoxic impact on breast MCF-7 was more than three folds less (IC50 79.55 ± 0.57 μg/ml) [Table 2].
Figure 1: The curve of dose response of hexane extracts of Avicennia marina against solid tumor cell lines (a) HCT-116, (b) HepG2, (c) MCF-7. Cells exposed to the extracts for 72 h. Cell viability was determined using Sulforhodamine-B-assay and data are expressed as the mean of three independent experiments; error bars were not shown to avoid the complexity

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Table 2: The (IC50 μg/ml) of hexane extracts of Avicennia marina against different solid tumor cell lines compared to doxorubicin as a positive control

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Detection of the morphological characteristics of apoptosis

The potential apoptotic impact of A.marina hexane extract evaluated on Human Colon “HCT-116,” Human Breast “MCF-7,” and Human Liver “HepG2” cancer cell lines. Cells exposed to determined concentration by IC50 of hexane extract for 72 h. The morphological changes of cancer cells induced by A.marina extract evaluated by cell shrinkage, pyknosis, membrane blebbing and chromatin condensation.[38] Accordingly, the results of the current study revealed that hexane extract has a weak ability to induce apoptosis, although the cells showed membrane blebbes in addition to apoptotic bodies. The effects of the hexane extract on different cancer cell types regarding the apoptosis were not significant [Figure 2].
Figure 2: Morphological changes of HCT-116, MCF-7 and HepG2 cells induced by the IC50 concentration of Hexane extract of Avicennia marina, stained with AO/EB. The images were taken using fluorescence microscopy at ×20. C=Control, no treated cells, T=Treated cells. MB=Membrane blebbing, CC=Chromatin condensation, EA=Early apoptosis, LA=Late apoptosis, AB=An apoptotic body, N=Necrosis. Scale bar: 2 μm

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Cell-cycle analysis

Flow cytometer used to identify the cell cycle phase that affected by A.marina hexane extract (80%). Results revealed that the extract has different impact mechanism depending on the cancer cell type. Where its impact was on HCT116 in G0-G1 phase, the extract showed the effect on MCF-7 and HepG2 cancer cells in S phase, of course, it should note that the effect on all cells was moderate compared to control group [Table 3] and [Figure 3], [Figure 4], [Figure 5].
Table 3: Effect of hexane extract of Avicennia marina on the cell cycle distribution of three tumor cell lines for 24 h compared with control cells

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Figure 3: Effect of hexane fraction of Avicennia marina aqueous ethanol crude extract on the cell cycle distribution of MCF-7, HCT-116, and HepG2 cancer cell lines. Cells were exposed to hexane extract for 48 h (B) and compared with cell control (A). Cell cycle distribution was determined using DNA cytometry analysis, and different cell phases plotted. (C) Percent of total events (n = 3)

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Figure 4: Chromatogram of hymecromone detected in hexane extract from the leaves of Avicennia marina

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Figure 5: Mass spectra and main fragment of hymecromone

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Liquid chromatography-mass spectrometry/mass spectrometry

LC-MS/MS profile for the hexane crude extracts reveals the presence of hymecromone the most critical compound for our study since it has been reported to have anticancer activity and used in chemotherapy. In addition to that, betaine molecule, which is useful in reserve osmosis in the plant, different ammonium, adduct resin for helping the plant to survive in high salinity. The chromatogram [Figure 4], mass spectra and the main fragments of hymecromone [Figure 5] and [Table 4] proofed the presence of hymecromone.
Table 4: Liquid chromatography/mass spectrometry-mass spectrometry profiling for the chemical composition of hexane crude extracts from the leaves of Avicennia marina

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 > Discussion Top


Plants have long used in folk medicines. Currently, many available drugs on pharmacy shelves are either natural products or their derivatives. In particular, A.marina has been widely used in folk medicine in China, India, and the Middle East to treat a wide range of disorders including cancer, ulcer, viral and skin diseases.[28],[39],[40],[41],[42] Moreover, recent scientific reports have demonstrated its antiproliferative activity against several cancer cells invitro[28],[42],[43] and invivo.[42] Whereas, the plants produce secondary metabolites as a result of adaptation mechanisms, which provide adjust to the change of the environment as well as to protect them from herbivores and insects. However, these secondary metabolites may contribute to the enhancement of the vital processes of human beings consuming plants. Therefore, the current study evaluated the antiproliferative effects of plant A.marina leaves hexane extract, grown under environmental stress (salty soil and high temperature).

Results revealed that the non-polar hexane extract showed cytotoxic activity against the tested cancer cell lines. However, one of the interesting observations is that extract has demonstrated antiproliferative activity at potency three folds higher on colon HCT116 cancer cells 23.7 ± 0.74 μg/ml compared to breast cancer cells MCF7 79.55 ± 0.57 μg/ml [Table 1]. Further investigation of hexane extract activity revealed its moderate ability to induce apoptosis responses in all tested cancer cell lines [Figure 2]. Which may go in line with the mechanism reported [44] for avoiding apoptosis via autophagy although the same author indicated the ability of the plant extract to induce apoptotic when blocking the autophagy mechanism.[28],[44] reported that the plant extract induces apoptotic in breast cancer cell line via the regulation of apoptosis P53 and Bcl 2 family proteins.

Moreover, hexane extract at equipotent concentrations interestingly exhibited a different cell cycle arrest pattern among these cell lines while G0-G1 phase arrest observed in hexane extract-exposed HCT116, S phase arrest detected in MCF-7 and HepG2 cell lines. The attempts to understand the ability of A. marina hexane fraction had been leading to expect that hexane extract may have the ability to activate cyclin D or E, CDK2 or CDK6, in addition to R point which has an essential role in cell cycle progression through the G1 phase.[45] Thus, further studies are needed to identify the activated pathway. Furthermore, the accumulation at S phase revealed that the extract might affect genetic material DNA especially since S phase is known as DNA damage checkpoint.[46] Subsequent studies have shown that p53 can stop or block the cell cycle at S phase checkpoint after DNA damage.[46] In the light of these data, the A.marina hexane extract may have a role in DNA degradation or p53 activation. Likewise, the A.marina extract reported shown to induced apoptotic through causing the DNA fragmentation in breast cancer cell line MDA-MB 231 and increasing the expression of P53 and reduction of Bcl2 proteins.[28] Similar, the isolated NFD compound arrest the cell cycle at S phase in the same cell lines.[28],[30]

The major difficulty is not to identify the biological mechanisms that have activated, but in the explanation of which molecule in the extract can activate such mechanisms. Consequently, the LC-MS/MS analysis was necessary to inspect the function-composition relationship. The LC/MS-MS analysis showed that the hexane extract contains Hymecromone molecule, which had identified for the first time in this plant species.[47] Hymecromone molecule known as a non-toxic dietary supplementary molecule even used in high concentration, in addition to that, it is already in use as an anticancer drug by inhibition the hyaluronic acid (HA) synthesis.[48] Therefore, the current study revealed that the anticancer activity of hexane extract might be due to the presence of Hymecromone.

While cytotoxicity involving one mechanism of action may explain the relative selectivity of hexane extract toward HCT116, the observed different patterns of cell cycle arrest as a pharmacological endpoint indicate the involvement of multiple mechanisms of action. These findings are compatible with the previous studies confirmed that the hymecromone could reduce cancer metastasis by inhibiting the synthesis of HA which promotes different pathways in cancer cells.[47] Furthermore, the attempts to understand the relationship between the composition of hexane extract and cell cycle looks like that it is far away to have a specific role in cell cycle inhibition despite the results showed cell cycle arrested in different stages.


 > Conclusion Top


Chemical analysis of hexane extract of A.marina by LC-M/MS showed that one chemical compound responsible for the anticancer activity of hexane extract. Furthermore, LC-MS/MS analysis indicates the presence of chemical constituents has role in treat salinity of the environment as a result of that salinity environment has no significant effects on the overall antiproliferative activity of A.marina. The selectivity of hexane extracts toward colon cancer cells may be advantageous due to relatively easier and direct access of drug via the oral route of administration.

Acknowledgment

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through General Research Project under grant number (R. G. P 1/9/38).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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