Anti-cancerous Activity of Mangosteen Pericarp Extract


 

Abstract

Garcinia mangostana (mangosteen) is a plant found in the tropical areas of South East Asia and extract from the pericarp of its fruit has many crucial functions and activities, it has been used as a traditional medicine to treat several diseases from a long time. Phytochemical analysis have revealed that they comprise a wide variety of secondary metabolites including both prenylated as well as oxygenated xanthones. These xanthones play an important role in several biological processes including anti- bacterial, anti-inflammatory and anti-cancerous effects. Recently anti-proliferative effects of 4 prenylated xanthones including alpha, beta, and gamma and beta methoxy mangostin have been identified in various cancer cells of the human. The three xanthones except for beta methoxy mangostin strongly contributed in inhibiting the growth of cell at low concentrations ranging from 5uM to 20uM in the DLD-1 cancer cells of human colon. Alpha mangostin is also responsible for inducing apoptosis by activation of certain intrinsic pathways like MAPKs (Mitogen Activated Protein Kinases) and Serine/Threonine kinase Akt. These studies and findings can possibly provide an authentic basis for xanthones development as an anticancer agent along with combination therapy with the other anticancer drugs.

  1. Introduction

From centuries mangosteen tree has been cultivated as a tropical fruit in tropical areas of the world. Mangosteen fruit is considered as the best fruit in taste the whole world, its white inner pulp is highly praised as one of the best tropical fruits in taste. String is known as Garcinia mangostana scientifically. Size of fruit ranges from 2.6 to 7.6 cm in its diameter approximately equal to the size of a tangerine. Size of the skin of the fruit ranges from 0.7 to 1.1 cm in thickness and it contains a pigment which is purple in colour. Mangosteen in apurb is comprised of 428 White coloured juicy segments also known as fruit portions. Pouch 25% of the total volume of the fruit is edible and the remaining is better and tough pericarp which represents a yellow resin (xanthones). Thousand years the skin bark and leaves of the mangosteen plant have been used for beneficial purposes as medicine for treating several diseases and for certain other therapeutic uses. Thick skin of mangosteen fruit has been used for treating diarrhoea, dysentery, intestinal ailments, skin ailments, fever and eczema.

                In some regions of the world the leaves of mangosteen plant are also used by natives in their tea for treating fever, thrush, dysentery and diarrhoea. Have also shown that the mangosteen bark concentrates are also beneficial and can be used to treat genito urinary afflictions along with certain other disease including stomatosis. Primitive medicinal plants have been observed and are more concerned topic of today's research to identify the factors which are potentially active in anticancer activity, many of the factors in the form of chemopreventive and therapeutic agents have been identified yet which are very helpful and valuable against anticancer activity. Anticancer drugs including etoposide camptothecin and pacelitaxel have been identified yet and are strongly contributing in anticancer activity. Has been shown by epidemiological studies that dietary phytochemicals contribute effectively in the prevention of cancer. Phenols are one of the best preventive agents which have both anticancer activity as well as antioxidative activity. These factors control the cancerous activity bye exhibiting and anti-proliferative effect ultimately leading towards the induction of apoptosis by targeting the mitochondria with the decline in the membrane potential ultimately leading towards the intrinsic apoptotic signal transduction activation. This review we are going to discuss about the anticancer activity of pericarp extract from mangosteen fruit.

 

  1. Xanthones

The pericarp of mangosteen fruit is comprised of an array of polyphenolic acids (Akao, Nakagawa, & Nozawa, 2008) which includes tannins and xanthones play a vital role in in protecting the plant against the infestations by bacteria, plant viruses, animal predation and insects during the immature period of the fruit (Lattanzio, Lattanzio, & Cardinali, 2006). Softening and colour changes in the fruit are the natural processes of ripening of fruit indicating that food is ready to eat and the development period of seeds have been completed. Pericarp constituents mainly xanthones phenols which are physically active mostly found in the restricted groups of plants naturally (Rai & Kon, 2013). About 50 (Gutierrez-Orozco & Failla, 2013) different type of xanthones have been identified yet in mangosteen and there are total of about 200 xanthones which are currently known (Gutierrez-Orozco & Failla, 2013). Tarpin oil group is the one main group which are contributing any applications of different functions in the cell like interacting with the signal transduction molecules and certain other proteins involved in the transition of mitochondria permeability.

 

  1. Prenylated Xanthones as Growth Inhibitors

A lot of studies have been conducted and they have shown that prenylated Xanthones (Khaw et al., 2014) important role as growth inhibitors. The four major prenylated Xanthones, also similar in structure involving alpha mangostin (P. Li, Tian, & Ma, 2014),  beta mangostin (Omer et al., 2017),  gamma mangostin (Chang & Yang, 2012),  methoxy beta mangostin  (Chaijaroenkul & Na-Bangchang, 2014) is implanted in an experiment to examine the effects of all these 4 prenylated Xanthones on the human colon cancer DLD-1 cells (Yamada et al., 2013) growth. All three mangostins including alpha, beta and gamma mangostin effectively contributed in inhibiting the growth of human colon cancer cells (Kuete et al., 2014) except for the methoxy beta mangostin. After lot of experiments it was concluded that antiproliferative effect of alpha mangostin is also known as the major constituent of pericarp extract (Ibrahim et al., 2016), it is because of apoptosis (Nikoletopoulou, Markaki, Palikaras, & Tavernarakis, 2013) it was analysed by using the DNA electrophoretic analysis (Ling & Ling, 2013) and Hoechst 33342 staining technique (Chan, Wilkinson, Paradis, & Lai, 2012). While comparing the alpha mangostin with the other anticancer drugs such as camptothecin (Govindan, 2014), actinomycin D (Paramanathan, Vladescu, McCauley, Rouzina, & Williams, 2012) and 5-FU (Venook et al., 2014) it was concluded that properties of alpha mangostin were more close to 5-FU (J. J. Wang, Shi, Zhang, & Sanderson, 2012) while on the other hand the morphological changes generated by alpha mangostin were totally different from those which were produced by 5-FU (Kumazaki et al., 2013).

 

  1. Apoptosis induction by alpha mangostin

Recent studies have shown that alpha mangostin is responsible for the activation (Lee et al., 2016) of caspase 3 and 9 (Ying et al., 2012) but it is not responsible in caspase 8 activation in HL60 cells (Y. Li et al., 2013) suggest that alpha mangostin may contribute in mediating the mitochondrial pathway which is involved in apoptotic process (Won et al., 2014). After 1 to 2 hour treatment certain parameters (Cha et al., 2012) of mitochondrial dysfunctions were observed, these parameters included accumulation of ROS, decline in intracellular ATP, loss of membrane potential cytochrome c / AIF (Okada et al., 2012) release and swelling, all of these factors clearly show that alpha mangostin preferably targets the mitochondria in its early stage (K. M. Chan et al., 2012).

Important fact is that hydroxyl group is replaced by methoxy group which results in the decline in the potency to cause the dysfunctioning of mitochondria (Romagnoli et al., 2013). Along with this it was also observed that decrease in the membrane potential of mitochondria was in an association with the cytotoxicity (Schirris et al., 2015). In addition to this it was also seen that with the help of intrinsic pathway in DLD 1 cells the alpha mangostin induced cell cycle arrest at G1/S as well as subsequent apoptosis with its aid (Syam et al., 2014), while on the other hand cell cycle arrest beta gamma mangostin was present at S phase (Chang & Yang, 2012). Apoptosis induced by alpha mangostin was mediated, along with the release of Endo-G with the help of independent pathway characterized by mitochondria. Endo-G (Kapoor, Rizvi, & Kakkar, 2013) is actually a 30 kD nuclease which is present in the mitochondria and it has the ability to induce fragmentation of the nucleosomal DNA (Manimekalai, Sivakumari, Ashok, & Rajesh, 2016).

Cell differentiation, cell growth, cell cycle, death and survival, all of these factors are controlled by many protein kinases serine/threonine. Regulatory proteins in the cells are (MAPKs) mitogen-activated protein kinases and Akt kinases. Among these specifically mitogen activated protein kinases are the more concerned family from serine and threonine protein kinases which are crucial in many cellular processes involving cell motility, death, cell differentiation and cell proliferation (M. Yang & Huang, 2015). On the other side Akt is another serine/threonine protein kinase as an association with cell growth, glycogen metabolism and survival of the cell. There are certain phytochemicals which have the ability to modulate the signalling pathways induced by mitogen activated protein kinases (del Reino et al., 2014) (MAPKs) and Akts contributing towards the inhibition of growth and death of the cell. These phytochemicals usually involves resveratrol, arucanolide and epigallocatechin 3 gallate (Kim, Quon, & Kim, 2014) which have the ability to inhibit cell growth and inducing apoptosis (Braicu, Gherman, Irimie, & Berindan-Neagoe, 2013).

It has been observed from the studies that the phosphorylation levels that after treating p38 and p-JNK with alpha mangostin they were modified but these modifications were not able to be explained properly. Recent studies have shown that alpha mangostin was able to elevate the expression of miRNA 143. Studies and research shows the expression of mi RNA is high (Di Leva & Croce, 2013) in normal cells while in case of human colon cancer tumors expression of mi RNA is remarkably in decreased concentration (Taniguchi et al., 2015). Alpha mangostin has an important role in elevating the expression levels of mi RNA 143 in the apoptotic cell death process by modifying the transcription (Kumazaki et al., 2013) or the upstream signals which are associated with the mi RNA 143 transcription factors.

  1. Alpha mangostin treatment in combination with anticancer drugs

Recent studies from the phytochemical (Da-Costa-Rocha, Bonnlaender, Sievers, Pischel, & Heinrich, 2014) analysis have shown that the efficacy of anticancer drugs and their metabolism is greatly affected by such substances (Chen et al., 2012) which are included in fruits and vegetables, set is based on the reason because many of the patients having cancer took folk medicines in addition to anticancer drugs and also used supplements along with anticancer drugs. That is why it is really important to study the association for interaction between the anticancer drugs and action of phytochemicals (Hosseini & Ghorbani, 2015). In addition to this, certain strategies which are aimed at enhancing the efficiency of therapeutic treatment methods of anticancer drugs as well as reduction in the side effects caused by these anticancer drugs (Parhi, Mohanty, & Sahoo, 2012) and involves the administration schedule and also its use in combination with certain phytochemicals for a beneficial and better treatment response. One of the most effective chemotherapeutic agent 5-FU (Nishida et al., 2012)which is used for colorectal adenocarcinoma has response rates of approximately 11% when what is used as a single agent (Ducreux et al., 2013).

An experiment was conducted on the synergistic effect on cell growth by using 5-FU in combination with alpha mangostin (Kumazaki et al., 2013). It was observed that 5-FU is responsible for the inhibition of cell growth which was due to the cell cycle arrest (Zhao, Fan, Hong, Li, & Wu, 2012) at the tested concentrations as no apoptotic activity was observed. The regions where alpha mangostin was present more than 15úM, apoptotic activity was observed (Luo, Fang, Ling, & Luo, 2019) while on the other side at the areas having low concentrations of alpha mangostin what is possible for causing cell cycle arrest similarly like the 5-FU.

That is why the synergistic effect resulted in the form of combined treatment at the total 2 and 5úM concentrations was due to the additional machinery enhancement ultimately leading towards the cell cycle arrest (Gu, Kaufman, Mavis, & Czuczman, 2017). Addition to this after 24 hours expression of cell cycle related proteins including c-Myc and cyclin D1 (Pestell, 2013) at total 5úM was reduced significantly as in comparison with the cell cycle related proteins found in single agent.

A lot of studies have suggested and supported the concept that it is possible that the mechanism characterized by alpha mangostin for growth suppression is totally different from that of 5-FU  at a ratio more than 15úM, is due to the reason that up regulation in the growth was obtained in small ratio by the combined treatment as compared to the single treatment with alpha mangostin which produced greater results and more growth inhibition (Ibrahim et al., 2016). Is also another think that it might be possible that the potent activity induced by apoptosis of alpha mangostin which was observed at ratio more than 15úM was not seen to be induced result of the combination with 5-FU at both of the ratios 7.5úM as well as 10úM. The medicine activated protein kinases and Akt signalling pathways activation, which can be modified by treating it with alpha mangostin at 20úM can be possibly reduced by treating it with a single treatment carried out by alpha mangostin or on the other hand 5-FU can be used for the same purpose. Therefore, phytochemicals are credible to exert a devastating effect on the efficacy of anticancer agents which solely depends on their concentrations by modifying the intracellular signalling pathways (Oon et al., 2015). Some of our recent studies have also shown the enhanced efficacy of alpha mangostin as in comparison with other anticancer agents (Xia, Chen, Gong, Chen, & Sun, 2016).

 

  1. In vivo cancer preventive effect

Recent studies have shown that in rat colon the alpha mangostin has short term chemopreventive effects on the protective plastic lesions (Suzui, Morioka, & Yoshimi, 2013) which work efficiently and were involved in the carcinogenesis (Fragoso, Romualdo, Ribeiro, & Barbisan, 2013) of the rat colon. A group of rats from 1-3 were given a subcutaneous injection which comprised of carcinogen 1, 2 dimethyl hydrogen for consecutive two weeks (Aranganathan & Nalini, 2013). Was observed that the dietary administration of alpha mangostin with the dose ratio of 0.02% and 0.05% was able to significantly inhibit the development of aberrant crypt foci induction against 0.02% alpha mangostin as compared to the dimethyl hydrazine treated group.in addition to this it was also seen that the group of rats which were treated with 0.05% of alpha mangostin had decline in the ratio of dysplastic foci and beta catenin accumulated crypts. Suggestions from the studies concluded that alpha mangostin has potent effects in the form of chemopreventive agent in short term colon carcinogenesis (Ibrahim et al., 2016) and longer exposure to the alpha mangostin may possibly result in the suppression of the development of tumor (P. Li et al., 2014).

  1. Immunomodulatory effect

Innate immunity the cell which are more responsible for maintaining the immune system involves natural killer cells and these cells are also responsible for performing their vital function in the eradication of tumor cells and certain other virus infected cells. After peak at about 15 years old the activity of natural killer cells tends towards the decline in its function and activity with the onset of aging (Nielsen, White, Goodier, & Riley, 2013). In today's world with the answer of aging the morbidity rate of people affected with cancer is also increasing at a great rate and this champion vision which might play its role in decreasing the activity of natural killer cells.

An experiment was conducted by using a mouse model to investigate the effect of alpha mangostin on the natural killer cells activity (Lee et al., 2016). In this experiment the alpha mangosteen enriched extract taken from the pericarp of mangosteen fruit including the alpha mangosteen about 80 to 90% and gamma mangostin about 5 to 10% was administrated to the mice every single day for the consecutive 30 days with different doses. By measuring the LDH of the incubation of YAC-1 cells (Narni-Mancinelli et al., 2012) and splenocytes the activity of natural killer cells was determined at the ratio of 1 to 50. It was observed that there were no allegations in the control group with 0mg/kg as compared to the significant elevation in the activities of the groups with 20 and 40 mg/kg ratios. Along with this significant increase in the activity of natural killer cells characterized by alpha and gamma mangostin was also seen in the human pilot study with the help of healthy people at the dose of 150 mg per day for consecutive 7 days per person (Shurovi, 2017).

Report has shown that lack of leukaemia cells activity contributes towards the autophagy and apoptosis (Torgersen & Simonsen, 2013). Studies have shown that alpha mangostin 20úM can play a vital role in treating the leukaemia cells and controlling the autophagy and apoptosis processes. This pericarp extract alpha mangostin is responsible for elevating the LC3-II and Beclin- 1 (Jiang, Shao, Wang, Yan, & Liu, 2012) levels progressing towards the decline in levels of p62 which is actually an autophagic protein and is degraded. Inhibition in the autophagic processes was shown to read the increased efficiency of alpha mangostin effect as a antitumor agent (Aisha, Abu-Salah, Ismail, & Majid, 2012) along with this it also suggest that it can play a vital role as an initial protective effect for controlling autophagy. In addition to this treatment with alpha mangostin was reported to induce cell cycle arrest in the G1 phase of cell division.

  1. Effects on Cancer development

Mangosteen pericarp extract is also responsible for anti-metastatic effects (Shibata, Matoba, Tosa, & Iinuma, 2013) along with apoptosis and autophagy induction the can be used as an alternative for treating metastasis (Hoshino et al., 2015) which is the major reason of that's because it is a major component to be found in the patients having cancer and causes about 90% of cancer related deaths. There are several different events which are collectively making metastatic processes these events usually involves migration surface and adhesion, cell invasion and extracellular matrix degradation. On this basis extract of mangosteen pericarp about 71.3 percent of alpha mangostin was very useful in the treatment to inhibit the migration of colorectal cells (Jung, Park, Jeon, & Han, 2015) of the carcinoma (Özdemir et al., 2014). It was also observed that mangosteen pericarp extract treatment was also responsible for the decline in in cologenicity as well as loss in the membrane potential of mitochondria and increment in caspase 3 and 7 levels.

Certain mechanisms have been identified to be related with anti-metastatic effect of alpha mangostin. Study was conducted in 2010 to investigate effects induced by alpha mangostin 5úM treatment, it was observed that there was decrease in the cell invasion, adhesion and migration of the lung cancer cells which is induced by (PMA) phorbol 12 myristate 13 acetate. It was observed that alpha mangostin treatment significantly reversed the PMA induced up regulation in the MMP-2 and MMP-9 expression protein activity and protein levels (Park et al., 2013). In addition to this mangosteen fruit pericarp was also reported to improve the (FAK) focal adhesion kinase and phosphorylation of ERK induced by PMA. Along with this it was also observed that alpha mangostin treatment attenuated the PMA induced nuclear translocation of NF-KB (J. Wang et al., 2014) and its binding to DNA.it was calculated from the studies that and how mangosteen treatment is responsible for the exhibition of its anti-metastatic effect with the help of the regulation of focal adhesion kinase (Wong et al., 2012) and ERK which are vital proteins responsible for the enhancement of nuclear translocation for NF-KB ultimately leading towards the induction in the expression MMPs.

Treatment with alpha mangostin 5uM was also reported and it contributed towards the decrease in migration of the cancer cells of pancreas. The process related to this effect caused decrease in the levels of MMP-2 and MMP-9, an elevation in the levels of E-cadherin, which is a protein responsible for playing a vital role in the epithelial cells by mediating cell-cell junctions, has been observed to be down-regulated in epithelial to the transitions in the mesenchymal cells (Scheel & Weinberg, 2012), along with this it also contributes towards the decline in the phosphorylation of ERK. Studies have shown that ERK plays crucial role in the induction of MMPs expression by activation of ETS, Decrease in its levels (Ahmad, Wang, Nair, & Kapila, 2012) might contribute towards lowering the levels of MMPs.

Certain studies have found that other concentrations of alpha mangostin like 8uM and 16 µM are responsible for decreased migration of the cancer cells of pancreas (Yuan, Wu, & Lu, 2013). The process related to this effect caused decrease in the levels of MMP-2 and MMP-9, an increase in E-cadherin (Canel, Serrels, Frame, & Brunton, 2013) levels, a diminution in N-cadherin levels along with a decrease in the phosphorylation of AKT.

It was also observed that α-mangostin treatment was also seen to up regulate the activity of caspase-3 and decrease in the levels of Bcl2 (Roberts et al., 2012). In addition to this, treatment with this extract (xanthone) obtained from mangosteen pericarp was seen to be responsible for inducing cell cycle arrest in the G1 phase (Q. Yang et al., 2013), along with this it also decreases the levels of cyclin D1. Furthermore, mangosteen pericarp extract was also observed to counter certain other cancer activities, like alpha mangostin was seen to inhibit the mutant iso citrate dehydrogenase 1, It also contributes in ROS modulation to prevent the activation of stellate cells of pancreas as their interaction with the cancer effected cells leads to the progression  of cancer.

  1. Conclusion

Alpha mangostin has remarkably high anti-proliferative activity because the IC50 of alpha mangostin is the same as 5-FU in the DLD-1 cells. Apoptosis is mainly responsible for alpha mangostin activity, it is responsible for playing its crucial role in certain biological processes involving activation of caspase proteins, signal transduction pathways and release of Endo-G. Along with this it has an interesting property that it targets the proteins which are involved in the permeability transition of the mitochondria which can possibly lead towards apoptosis and cell cycle arrest. Recently panaxanthone was identified which contains 80% to 90% alpha mangostin and 5% to 10% gamma mangostin and it has been assessed to be safe by the help of a conventional safety test by using a mouse model. The safety and clinical trials for using Panaxanthone commercially are still under process and it has promising results in effectively coping up against the cancer and act as a cancer preventive and therapeutic agent.

 

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