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Anti-Cancer Agents in Medicinal Chemistry, 2014, 14, 750-755

Damnacanthal: A Promising Compound as a Medicinal Anthraquinone Nadiah Abu1,2, Norlaily Mohd Ali1, Wan Yong Ho3, Swee Keong Yeap4, Muhammad Yusran Abdul Aziz1 and Noorjahan Banu Alitheen1,* 1

Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia; 2Bright Sparks Unit, Universiti Malaya, 50603 Kuala Lumpur, Malaysia; 3The University of Nottingham Malaysia Campus, 43500 Semenyih, Malaysia; 4Institut of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Malaysia Abstract: The Noni fruit, or scientifically known as Morinda citrifolia can be found in various parts of the world, especially in the pacific region. It is a small evergreen bushy-like tree originated from the Rubiaceae family. The plant has been used by polynesians as a medicinal herb for more than 2000 years. A substantial amount of phytochemicals can be found in the roots of this plant. Among all, damnacanthal has been found to be the most interesting, versatile and potent compound. Damnacanthal or chemically known as, 3 hydroxy-1-methoxyanthraquinone -2-caboxaldehyde (C16H10O 5), appears as pale yellow crystals with a melting point of 210-211°C. This compound is of particular interest due to its striking pharmacological properties. Damnacanthal was shown to inhibit the oncogene Ras, p56lck tyrosine kinase, NF-KB pathway and induce apoptosis in vitro. This review aims to discuss the biological properties of damnacanthal, specifically on its anti-cancer activity that has been reported.

Keywords: Anti-cancer, anti-inflammation, damnacanthal, morinda citrifolia, noni, pharmacology. 1. INTRODUCTION Most of the drugs discovered nowadays are largely derived from natural sources [1, 2]. Nevertheless, despite the hype and proven success in the past years, the use of natural products as a preliminary drug screening have decreased [2]. This is due to the disadvantages in handling natural products such as lack in accessibility, difficulties in comprehending the chemistry involved, as well as the tediousness of working with natural products [2, 3]. Therefore, isolating a particular compound from a natural source and testing its bioactivities may serve as a preliminary screening before proceeding to chemical synthesis. Among the plants that have been thoroughly explored and studied is the noni fruit. The noni fruit or scientifically known as Morinda citrifolia, has been the center focus of several international research groups in the past few years. The wide spectrum of biological applications that the noni fruit has been implemented in makes it even more interesting [4]. The noni fruit is consumed in various parts of the world including Polynesia, Australia, Hawaii and some parts of the pacific islands [5]. Its tree is physically known as a stout, evergreen bushy-like plant [6]. This fruit is traditionally used to treat a broad number of diseases such as cancer, diabetes and inflammation [6, 7]. As presented in Table 1, Morinda citrifolia can be found in numerous places and can be known as multiple names depending on the locality. There are numerous compounds that can be extracted from the roots of Morinda Citrifolia, including the anthraquinone, damnacanthal [8]. Damnacanthal can be physically identified as pale yellow crystals. The chemical and physical properties of damnacanthal can be found in Table 2 and the molecular structure of damnacanthal is depicted in Fig. 1. 2. EXTRACTION OF DAMNACANTHAL There are several methods that can be attempted to extract damnacanthal from the Morinda species. The standard way of extracting Damnacanthal is by the conventional solvent extraction [9]. The raw samples can first be extracted via methanol and purified using a silica-based column chromatography [9]. The

*Address correspondence to this author at the Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia; Tel: 03-894674 71; Fax: 03-8946 7510; E-mail: [email protected] 1875-5992/14 $58.00+.00

resulted fractions are then identified by TLC and can be further purified to obtain pure damnacanthal [9]. Table 1.

Different names of Morinda citrifolia in various parts of the world.

Location

Names

Hawaii

Noni

Polynesia Puerto Rico Malaysia

Mengkudu

Indonesia Australia

Indian Mulberry

Florida India Australia

Cheesefruit

Cayman Islands

Hog Apple

Jamaica Tahiti

Nono

French West Indies

Belimbi

French West Indies

Pomme-macaque

El Salvador

Rhubarbe caraïbe

Table 2.

Chemical and Physical Properties of Damnacanthal. Property

Details

Molecular Weight

282.2476 [g/mol]

Molecular Formula

C16H10O5

Physical Appearance

Pale Yellow Solid

Apart from the standard methanol extraction procedure, another way reported for extraction of damnacanthal is by using MicelleMediated Separation [10]. This method was essayed and optimized by Kiathevest et al. in 2009. The roots of Morinda citrifolia were © 2014 Bentham Science Publishers

Damnacanthal: A Promising Compound as a Medicinal Anthraquinone

O OH O O

O

Fig. (1). Molecular structure of damnacanthal.

grounded by liquid nitrogen prior to extraction via the micellemediated separation. This procedure utilized non-ionic surfactants such as Triton-X or GenapolX-080 to separate the sample into two phases at high temperature [10]. After the micelle-mediated extraction is completed, the end products were further extracted using Micelle-mediated pressurized hot water extraction (MMPHWE) [10]. Afterwards, the extract containing damnacanthal was concentrated using CPC (Cloud Point Concentration) and then further analyzed by HPLC [10]. This overall method was proven to be more economical, safer and less time consuming compared to the conventional solvent extraction process [10]. Another way to extract damnacanthal is by using subcritical water extraction. This method was reported by Anekpankul et al. in 2007 [8]. Subcritical water refers to the state of the water in between the boiling temperature (100oC) and critical temperature (374ºC) [8, 11]. The condition of the water at this temperature is less polar due to the breakage of hydrogen bonds within the water molecules [8]. It was reported that the optimum temperature of the water that produced the highest amount of damnacanthal was at 170ºC [8, 11]. This method resulted in more compound being extracted as to the standard methanol extraction [11]. It has also been put forward by Witayasinthana et al. [12] that one of the methods for extracting damnacanthal from the roots of Morinda citrifolia is by the Microwave-Assisted Extraction. Noticing that different parameters would influence efficiency of the extraction, the group has optimized the extraction condition to a 3-minute process at the temperature of 120ºC and a solvent to sample ratio of 1:100 for high recovery of the compound [12]. Table 3 summarizes the methods of extracting Damnacanthal that has been reported. 3. ANTI-CANCER PROPERTIES 3.1. Immunomodulation One of the characteristics that makes a drug fascinating and worth exploring is the effect it has on the immune system. Enhancing the immune system by promoting thymus growth could be beneficial for anti-aging and disease prevention. A pharmacological study conducted by Alitheen et al. (2010) suggested that damnacanthal has an interesting immunomodulatory potential [13]. Damnacanthal induced proliferation of mice thymocytes at a dose- and timedependent modus and was not toxic to the cells even at high concentrations [13]. Maximum growth was found to be at 24 hours with treatment at 30 µg/ml [13]. Furthermore, this compound also exhibited the same effect towards human peripheral blood mononuclear Table 3.

Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 5

cells (PBMC) [13]. Damnacanthal-treated PBMC exhibited a higher percentage of proliferation in the G2/M phase compared to the untreated cells [13]. The proliferation and differentiation of lymphocytes is directly regulated by certain cytokines. Thus, it was anticipated that there would be an increment of induced Interleukin 2 and 12 upon treatment by damnacanthal [13]. This was proven when 151.7 pg/mL of damnacanthal induced the secretion of IL-2 (interleukin 2) after 24 hours. This compound also increased the amount of IL-12 to 4.9 fold higher than the negative control at three different time points [13]. These results suggested that Damnacanthal has the prospective to become a drug that improves the immune system [13]. Cytokines act as important mediators in the immune system. Interleukin 12 in particular, once it is activated it will activate the JAK/STAT pathway [14]. Downstream of the STAT pathway, the NK cells and the Th1 response will also be activated [14]. These are the main players in anti-tumor immunity [14, 15]. Likewise, IL-2 is also an important cytokine that plays a role in improving the immune system. IL-2 can be produced by either NK (natural killer) cells or T cells [16]. Once it is activated, IL-2 will act upon several target cells including NK cells, B cells, Treg cells and monocytes [16]. This will further boost the immune system against cancer cells. Furthermore, IL-2 is also used as an alternative immunotherapy in treating several metastatic cancer [17]. 3.2. Anti-Inflammatory Activity One of the most promising properties of damnacanthal is its anti-inflammatory effect. Several researches have conducted experiments to disclose this property. In a formalin test conducted by Okusada et al. in 2011, damnacanthal only notably inhibited pain-related behavior in the late phase of the experiment in a dosedependent manner [18]. Additionally there was a significant inhibition of paw edema induced by histamine when tested with damnacanthal [18, 19]. This compound also down-regulated the expression and activity of lipopolysaccharide-induced nuclear factor-κB (NF-κB) (nuclear factor kappa-light-chain-enhancer of activated B cells) [19]. This eventually led to the inhibition of the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and other pro-inflammatory cytokines when treated with damnacanthal [19]. 3.3. Ras Inhibitor Interestingly, at the molecular level, damnacanthal was shown to be prominently involved in the regulation of the protein Ras. Ras is among the commonly mutated protein in cancer [20]. It loses the ability be inactivated once its is mutated and thus contributing to the development of tumors [20]. In a large-scale screening carried out Hiramitsu et al. in 1993, damnacanthal was the most efficient in inhibiting Ras among a panel of 500 plant-based extracts [21]. The compound inhibited the activation of Ras at a concentration of 8 µg/ml [22]. 3.4. Tyrosine Kinase Inhibitor Tyrosine kinase is an enzyme that activates the signal transduction cascades through phosphorylation of proteins. A number of anthraquinones exhibited inhibitory effect against

A summary of methods to extract damancanthal.

Method

Description

Conventional Solvent Extraction

-Via methanol

Micelle-mediated Separation

Advantages/Disadvantages

-Utilizes non-ionic surfactants

-Less time consuming

-Further extracted using micelle-mediated pressurized hot water extraction

-More Economical

-Concentrated via Cloud Point Concentration Subcritical Water Extraction

-Highest yield at 170 ºC

Microwave-Assisted Extraction

-A 3 minute extraction at 120 ºC

751

-Higher yield than solvent extraction

752 Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 5

tyrosine kinase and damnacanthal is one of them. Damnacanthal has been reported to be involved in the regulation of rapid tissue responses such as contraction [23] and delayed responses such as gene transcription [24] apoptosis [25] and cell proliferation [26]. Faltynek et al. claimed that damnacanthal acted as the most potent Lck-directed inhibitor in Src kinase family. Studies also claimed that damnacanthal showed potent and selective inhibitory effect towards p56lck tyrosine kinase activity [27] and Src tyrosine kinases [28]. Besides, damnacanthal was also used as an inhibitor for Src tyrosine kinase in a variety of tissues [29]. 3.5. Photodynamic Action Since damnacanthal is a tyrosine kinase inhibitor, its mechanism is largely dependent on electron transfers [30]. Antitumor drugs heavily rely on the electron transfer process and generation of reactive oxygen species (ROS) [30]. Damnacanthal was shown to possess photodynamic properties that depends mostly on light [30]. Rajendran et al. (2004) conducted a study on the photodynamic actions that damnacanthal may possess. The photophysical properties that damnacanthal possessed is of both type 1 and type 2 reactions [30]. This study showed that damnacanthal was able to effectively generate reactive oxygen species (ROS) [30]. This is one of the most important properties in administering photodynamic therapy. Photodynamic therapy is being extensively used to treat cancer [31]. This therapy induces toxicity on cancer cells, damages to the vasculature system in tumors and inflammation [31]. Photodynamic therapy provides another alternative as to conventional invasive treatments. This method produces harmful ROS that will kill cancer cells either by apoptosis or necrosis [32]. ROS will only be produced if the photosensitizers are coupled together with light and oxygen [32]. 3.6. Induction of Apoptosis Damnacanthal was tested on several different cell lines including, human colorectal cancer cell lines, HCT-116 and SW480, human liver adenocarcinoma cell line, SKHep1, leukemia cell lines, Wehi-3B and HL-60 and also pancreatic cancer cell lines PANC-1 and PNS [9, 13, 33]. It was shown that in HCT-116 and SW480 cell lines, damnacanthal halted the cell cycle process in the S/G1 and G1/G2 phases [19]. Added to that, Damnacanthal also significantly increased the induction of caspase 3/7 in both HCT116 and SW480 cell lines [19]. The molecular mechanism by which damnacanthal induced cell death in HCT-116 cell line was investigated. NAG-1, a pro-apoptotic protein, was induced in a concentration and time-dependent way [19]. Since there was an arrest in the cell cycle progression, the treated cells were tested for the presence of cyclins. At the concentration of 10 µM of damnacanthal, the presence of Cyclin D1 was reduced [19]. Interestingly, the expression of p21 and p53 in treated cells remained unaffected [19]. Additionally, the cleavage of PARP (Poly (ADP-ribose) polymerase) was seen at the 10 µ M HCT-116 treated cells [33]. Damnacanthal was also shown to be toxic towards SKHep1 cells [34]. This cytocidal effect was further confirmed when the damnacanthal-treated cells produced fragmented oligonucleosomal DNA [9]. The pro-apoptotic properties of damnacanthal were prominently apparent when the population of cells increased after the addition of caspase 3 and caspase 9 inhibitors [9]. To further elucidate the apoptotic mechanism, two different pathway mechanisms were tested. It was shown that damnacanthal activated the p38 MAPK (Mitogen-activated protein kinases) pathway in SKHep1 cells [9]. Downstream of p38 MAPK protein, the ATF-2 (activating transcription factor 2) protein was also activated and phosphorylated [9]. Additionally, the TRAIL (TNF-related apoptosisinducing ligand) and TNF-α (tumor necrosis factor alpha) proteins were also activated in the presence of damnacanthal [9]. When these proteins are activated, the expression of DR5 and TNF-R1

Abu et al.

were also upregulated in SKHep1 cells [9]. From this study, it was suggested that the primary apoptotic mechanism in damnacanthalinduced cells was the p38 MAPK-p53 pathway [9]. It was reported that damnacanthal did not alter the level of expression of p53 upon treatment in cancer cells [19]. Surprisingly, Lin et al. reported that damnacanthal acted via the p38-MAPK-p53 pathway [9]. A plausible relation that can be deduced is that, the doses of damnacanthal used in these two experiments were different. Nualsanit et al. used a very low concentration of damnacanthal, ranging from 0.1-10 µM [19]. On the other hand, Lin et al. performed the experiment using a much higher dose, at 38-85 µM [9]. The amount of cytotoxic agent introduced in the cells could affect the level of p53 [35]. From this observation, it can be suggest that the higher the dose of damnacanthal, the more likely it will induce the activation of p53. 3.7. Anti-migration Properties In further proving whether or not Damnacanthal has an antitumorigenic potential, Nualsanit et al. performed a colony efficiency assay where damnacanthal decreased the colony number in HCT-116 cells in a dose-dependent manner [19]. Additionally, the clonogenic potential of cells treated with damnacanthal reduced significantly at both 10 µM and 50 µM concentrations [19]. In the migration assay, damnacanthal at the concentration of 10 µM and 50 µM inhibited cell migration in the wound healing repair assay even after 48 hours [19]. This indicated that damnacanthal has potential anti-migration capabilities [36]. Metastasis is a multi-step process whereby cancer cells form secondary tumors at a distant site than the primary tumor [37]. This process is the main cause of cancer-related fatalities [37, 38]. The ability of cancer cells to migrate marks the initial steps of metastasis [38]. Therefore, it is imperative to prevent cancer cells from migrating, and ultimately halt the metastatic process altogether. Damnacanthal has the potential to not only kill cancer cells, but also avert the cells from metastasizing. 3.8. Schematic Representation of Apoptosis Damnacanthal has been proven to possess several important properties as to what an anti-cancer drug should have. Firstly, damnacanthal was proven to inhibit the p56lck tyrosine kinase activity (Fig. 2). P56lck (lymphocyte specific tyrosine kinase) is a src tyrosine kinase that functions in the development of T cells [39, 40]. The inhibition of this protein could help in the treatment of Tcell based leukemia or lymphomas [27]. Additionally, it was reported by Park et al. that with the absence of p56lck, the induced apoptosis mechanism is more significant [41]. This proto-oncogene can be found in several cancer types and has been found to contribute to metastasis [40, 42, 43]. P56lck was found to be involved in breast cancer migration through inducing the secretion of urokinase plasminogen activator [44].Therefore, the importance to inhibit this protein is critical especially, in preventing the establishment of secondary tumors. Once the lck tyrosine kinase is activated, along with the formation complex in the T-cell receptor, it will activate a downstream pathway involving the protein ras [45]. Ras is a well-known oncoprotein with three isoforms, N-Ras, H-Ras and K-Ras [46]. The ras pathway is elaborate and intertwined with other important pathways such as, MAPK and cell cycle pathways [20, 47]. The activation of ras will trigger the MAPK/ERK cascade [47, 48]. This will ultimately lead to the transcription of several pro-survival genes including, c-jun, c-fos and c-myc [47]. Damnacanthal’s ability to inhibit p56lck and ras is a promising attribute especially in treating T-cells-related cancers. The p38 MAPK pathway on the other hand, can be activated by a various of stimuli including pro-inflammatory cytokines and stress [49]. This pathway is generally regarded as being antiproliferative upon induction [50]. The p38 MAPK pathway can indirectly regulate the activity of p53 and other mitochondrial

Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 5

Damnacanthal: A Promising Compound as a Medicinal Anthraquinone

753

Damnacanthal

p56lck

p38

NF-KB

ATF2

IP3+DAG

p53 COX-2 Bax

DR5

Ras

iNOS

TNF-R1

Cytochrome C

MEK Survival/Pro liferation

Caspase 8

Caspase 9

Inflammation

Caspase 3 Apoptosis

Fig. (2). A schematic representation of the possible pathways in damnacanthal-induced apoptosis.

Table 4.

A summary of bioactivities of damnacanthal.

Properties

Description •

Inhibited pain-inflicted behavior in mice.

•

Down-regulated pro-inflammatory mediators and the NF-KB pathway.

Immunomodulation

•

Induced proliferating mice thymocytes and PBMC

Anti-cancer

•

Ras inhibitor

•

Inhibited p56lck tyrosine kinase

•

Possess photodynamic properties

•

Inhibited several cancer cell lines

Anti-inflammatory

Cell Line

IC50 (µg/ml)

HCT-116

< 29

SW480

< 29

SKHep1

23.99

HL-60

4.2 ± 0.1

Wehi-3B

3.3 ± 0.5

Panc-1

1.26

PSN-1

1.07

CEM-SS

8.5 ± 0.5

related proteins eventually leading to the activation of apoptosis. Damnacanthal induces both the extrinsic and intrinsic apoptosis pathways through the p38 MAPK pathway. Furthermore, the NFKB pathway is commonly associated with inflammation [51]. Inflammation has been found to accelerate the metastasis process by providing a pro-growth microenvironment once it is activated [52]. Thus, when damnacanthal down-regulates the NF-KB pathway, the chance of cancer cells to metastasize also reduces. 4. CONCLUSIONS Humans have always opted for natural-based remedies to treat ailments and illnesses. In fact some of the most used drugs today

are derived from natural sources such as paclitaxel and doxorubicin. Morinda citrofilia is an interesting plant that has been extensively used in the pacific region as a traditional remedy. Damnacanthal, an anthraquinone derived from Morinda citrifolia has gained a lot of attention in the past few years. Multiple studies have undergone immense research just to discover the wonder properties of damnacanthal. As shown in Table 4, Damnacanthal has a lot to promise in becoming a viable anti-cancer agent. Damnacanthal can be used as an anti-inflammatory agent and can modulate the immune system. This compound inhibits tyrosine kinase and ras, possesses photodynamic action and induces apoptosis in vitro. As promising as it may appear, damnacanthal is indeed an interesting

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Abu et al.

anthraquinone that can be further developed into the commercial line. However, more in depth research is needed to actually gain a deeper understanding of how this compound really functions.

[19]

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.

[20]

ACKNOWLEDGEMENTS Declared none.

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Damnacanthal: A Promising Compound as a Medicinal Anthraquinone

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Received: July 22, 2013

Revised: October 11, 2013

Accepted: October 13, 2013

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