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Journal of Parenteral and Enteral Nutrition
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Original Communications

Feasibility Evaluation of Emodin (Rhubarb Extract) as an Inhibitor of Pancreatic Cancer Cell Proliferation In Vitro

Jun Cai, MD, Anthony Razzak, BS, Justin Hering, MD, Abdul Saed, MD, Tricia A. Babcock, MS, Scott Helton, MD and N. Joseph Espat, MD, MS, FACS

From the Department of Surgery, The University of Illinois at Chicago.

Address correspondence to: N. Joseph Espat, MD, MS, FACS, Roger Williams Medical Center, 825 Chalkstone Avenue, Prior 4, Providence, RI 02908; e-mail: jespat{at}hepaticsurgery.com.

Emodin is a commonly used traditional herbal treatment in China, including use for pancreatic malignancy. In this study, the potential for emodin to inhibit pancreatic cancer cell proliferation was examined using 4 human pancreatic adenocarcinoma cell lines: Mia Paca-2, BxPC-3, Panc-1, and L3.6pl. WST-1 proliferation, propidium iodide flow cytometry cell cycle analysis, and poly-ADP-ribose polymerase (PARP) Western blot analysis were performed. Forty-eight-hour treatment with 50 µM emodin inhibited proliferation in Mia Paca-2 cells by 42%, BxPc-3 by 38%, L3.6pl by 56%, and Panc-1 by 18% (all P < .01). In three-fourths of the cell lines, emodin treatment resulted in an increase (from 4.7% to 22%) in the cell population number in apoptosis when measured by flow cytometric analysis. Mia Paca-2 revealed a significant PARP cleavage product when compared with control. These feasibility experiments provide initial evidence that emodin exerts an antiproliferative effect, likely through apoptosis induction-related mechanism(s), that is reproducible in various human pancreatic cancer cell lines.

Key Words: emodin • pancreatic cancer • cellular proliferation • apoptosis

Emodin is a commonly used traditional herbal treatment in China, including use for pancreatic malignancy. Pancreatic cancer is one of the leading causes of cancer death in industrialized nations, and the incidence in developed areas in China, such as Beijing and Shanghai, has increased annually. Pancreatic adenocarcinoma remains an almost universally fatal disease that results in only an approximate 5% long-term survival, even when surgically resected. Moreover, for most of the approximately 30,000 annual cases, about 80% of patients already have locally advanced unresectable or distant metastatic disease that precludes operative resection at the time of initial presentation.1 As such, treatment options for these patients are limited to chemotherapy alone or combined chemotherapy and radiation. In the past decade, even with the advent of novel agents and their combinations, only an incremental increase in survival has been achieved, such that the most recent results of the GEM-CAP trial reported a median survival improvement from 6 months to slightly more than 8.5 months.2 Thus, it is crucially important to develop improved therapeutic strategies for the management of pancreatic cancer.

It is well known that growth inhibition and apoptosis are important determinants of the tumor response to chemotherapeutic agents.3-5 Therefore, compounds that induce cell-cycle arrest and apoptosis may potentially provide an additive or synergistic anticancer effect in the treatment of pancreatic cancer. Natural herbal medicines such as Rheum palmatum L (Polygonaceae) are traditionally applied in cancer therapy in Chinese medicine. Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is an active constituent isolated from the root of R palmatum L6 and is the main effective component of some Chinese herbs, such as rhubarb and aloe. Pharmacological studies have demonstrated that emodin possesses antibacterial,7 anti-inflammatory,8 immunosuppressive,9 vasorelaxant,10 antiulcerogenic,11 and anticancer effects. Previous studies have demonstrated that emodin inhibits cell growth in several types of tumor cells.4,12-18 Relevant to its antiproliferative activity, emodin is a potent inhibitor of tyrosine kinase19 and was shown to suppress HER-2/neu tyrosine kinase activity in HER-2/neu–overexpressing human breast and lung cancer cells in vitro, and also inhibition of malignant transformation and metastasis-associated properties of HER-2/neu-overexpression breast cancer cells in vivo. Previously, it has been reported that emodin can enhance the sensitivity of malignant cells to chemotherapeutic agents.15,20,21 However, the antiproliferative effects of emodin have not been well evaluated in human pancreatic adenocarcinoma. This potential novel approach may be synergistic or additive in the setting of consolidation therapies that use cytotoxic chemotherapy. In these experiments, the potential for emodin to inhibit pancreatic cancer cell proliferation was examined.


   Materials and Methods
Top
Materials and Methods
Results
 Discussion
 
Cell Culture Model and Reagents
Four human pancreatic adenocarcinoma cell lines were included: Mia Paca-2 and BxPC-3 (American Type Culture Collection, Rockville, MD), and Panc-1 and L3.6pl (gift from Gary Gallick, PhD, MD Anderson Cancer Center, Houston, TX). The cell proliferation reagent WST-1 kit was purchased from Roche Applied Science (Indianapolis, IN). Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) was purchased from Sigma Chemical Co (St Louis, MO).

Cell Culture
The pancreatic adenocarcinoma cells were cultured in Dulbecco's modified Eagle's medium (Mediatech, Manassas, VA), supplemented by 10% fetal bovine serum, 100 U/mL penicillin, and 100 µg/mL streptomycin at 37°C in a humidified atmosphere comprising 95% and 5% CO2. Trypsin-EDTA was used for cell harvest and passage.

Time and Dose Curves
All cell lines were treated with emodin at 12.5, 25, or 50 µM or media. Treatment times were 24, 48, or 72 hours. Cell proliferation studies were performed after the respective treatment schedule.

Cell Proliferation Assay
The WST-1 kit was used according to the manufacturer's standard protocol (Roche Applied Science). In brief, cells were seeded into 96-well plates at a density of 2 x 104 cells/well. After 24 hours in culture, the cells were treated with 12.5, 25, and 50 µM emodin (reconstituted in DMSO) at time points of 24, 48, and 72 hours. The same DMSO concentrations found in the 50-µM emodin group were used in the control group. Control-sample wells consisting of cells with media alone allowed a percentage-of-control calculation to be performed for each treatment. Cell proliferation was evaluated after emodin treatment. In brief, the concentration of WST-1 reagent was added to the cell amount of sample. The background was calculated using media and WST-1 reagent alone. After incubation for 4 hours at 37°C, the relative absorbance was measured with the ELx 808 Ultra Microplate Reader (Bio-TEK Instruments Inc, Winooski, VT) at 450 nm.

Cell Protein Extraction Protocol
After treatment, the cells destined for protein analysis were first washed twice with phosphate-buffered saline (PBS). Nuclear extracts (for poly-ADP-ribose polymerase [PARP] cleavage expression) were collected using the reagents and the protocol provided by the Nuclear Extract Kit (Active Motif, LLC, Carlsbad, CA). Total protein concentrations were determined using the DC protein assay (Biorad, Hercules, CA) and were then stored at –80°C for Western blot analysis.

Western Blot Protocol
For each nuclear extract sample, 40 µg of protein was added to each lane. Cell extracts were boiled for 5 minutes prior to loading on a 7.5% sodium dodecyl sulfate polyacrylamide gel electrophoresis gel and then transferred to a nitrocellulose membrane. The membranes were placed in a blocking solution (5% w/v nonfat dry milk in 1x Tris-buffered saline [TBS] with 0.1% Tween-20) for 1 hour. The blot membrane was then incubated with cleaved PARP (Asp 214, 1:1000 dilution) primary antibody overnight at 4°C, washed 3 times with TBS/T, and then incubated with a horseradish peroxidase–conjugated secondary antibody. After washing, the membrane was visualized with 10 mL electrochemiluminescence detection reagent and exposed to x-ray film for 10-60 seconds.

Cell-Cycle Analysis by Propidium Iodide Flow Cytometry
The protocol was performed as previously described. Emodin was diluted in culture media to 50 µm. Samples were harvested after 48 hours of continuous drug treatment. At harvest, cells were washed with PBS prior to and following trypsinization, then fixed in 70% ethanol, added dropwise with continuous vortexing to prevent clump formation, and stored at –20°C. All floating cells were conserved. Upon staining, samples were spun and resuspended in citrate buffer. Propidium iodide (PI) staining solution (PI/RNase Staining Buffer; BD Biosciences, Franklin Lakes, NJ). Samples were then gently centrifuged, and excess supernatant was aspirated. Samples were resuspended in the remaining volume, filtered, and analyzed by flow cytometry of the FL-2 area. Sample size was approximately 106 cells. Total DNA content was measured on a Coulter Epics Elite ESP flow cytometry machine (Coulter Corp, Hialeah, FL) with a minimum of 104 events counted. FL-2 area PI histograms were analyzed with Multi-Cycle AV software (Phoenix Flow Systems, San Diego, CA).


Figure 1
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  		Figure 1. Mia Paca cell line: 24-hour, 48-hour, and 72-hour treatment time points. All emodin concentrations are percentage of control (media only).

 
Statistical Analysis
All experiments were performed, at minimum, in triplicate. They were analyzed using the SPSS statistics program (Chicago, IL). Data are presented as the means ± standard error when possible. The data were analyzed by 1-way ANOVA, as well as additional ANOVA post hoc analysis (Tukey, Scheffé, and least square difference) as appropriate. Statistical significance was defined as P < .05 unless otherwise stated.


   Results
Top
Materials and Methods
 Results
Discussion
 
A significant (P < .05) time- and dose-dependent decrease in cellular proliferation was observed with 4 distinct pancreatic cancer cell lines (Figures 1, 2, 3, 4). In Figure 1, Mia Paca-2 cells show an optimal effect at 48 hours. The 50-µM concentration shows the greatest inhibition of cellular proliferation. In Figure 2, the L3.6pl cell line shows a time and dose-dependent inhibitory response to emodin treatment. Again, the strongest inhibition takes place at 72 hours with the 50-µM concentration. The Panc-1 cell line was more resistant to emodin treatment. Still, at 72 hours, there was significant (P < .001) inhibition of cellular growth. Conversely, the BxPC-3 pancreatic cancer cell line was highly susceptible to emodin treatment (Figure 4). At 24 hours, we saw significant (P < .001) inhibition of cellular proliferation. The inhibition was dose- and time-dependent.


Figure 2
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  		Figure 2. L3.6pl cell line: 24-hour, 48-hour, and 72-hour treatment time points. All emodin concentrations are percentage of control (media only).

 

Figure 3
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  		Figure 3. Panc-1 cell line: 24-hour, 48-hour, and 72-hour treatment time points. All emodin concentrations are percentage of control (media only).

 

Figure 4
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  		Figure 4. BxPC-3 cell line: 24-hour, 48-hour, and 72-hour treatment time points. All emodin concentrations are percentage of control (media only).

 
In particular, significant effects were seen across all cell lines in comparison to control DMSO treatment and were observed at 48 hours at an emodin concentration of 50 µM. These experiments demonstrated that at the 48-hour treatment, 50 µM emodin inhibited proliferation in Mia Paca-2 cells by 42%, BxPc-3 by 38%, L3.6pl by 56%, and Panc-1 by 18% (all P < .01). All data are represented in table form (Tables 1, 2, 3).


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  		Table 1. Twenty-four Hour Percentage Cellular Proliferation Compared With Control (Media)

 

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  		Table 2. Forty-eight Hour Percentage Cellular Proliferation Compared With Control (Media)

 

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  		Table 3. Seventy-two Hour Percentage Cellular Proliferation Compared With Control (Media)

 

To ensure that the antiproliferation effects of emodin were not from toxicity but rather apoptosis, Western blot analysis for PARP cleavage was performed on the Mia Paca-2 cell line (Figure 5). Mia Paca-2 cells treated with emodin at 50 µM were the highest in cleaved PARP expression when compared with media and DMSO treatment.


Figure 5
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  		Figure 5. Western blot analysis. Mia Paca-2 nuclear extract, 24-hour emodin treatment.

 
PI flow cytometric analysis of Mia Paca-2, BxPc3, Panc-1, and L3.6pl cells after treatment with media, DMSO, and emodin are presented in Figure 6. The first large spike in each control plot represents the G1 phase (2n) of the cell cycle, and the following plateau represents the S-phase. The large second spike represents the G2 phase (4n). The percentage apoptosis is presented in Table 4. In three-fourths of the cell lines, emodin treatment resulted in a 4.7%-22% increase in the number of cell population in apoptosis.


Figure 6
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  		Figure 6. Propidium iodide flow cytometric analysis, 48-hour treatment.

 

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  		Table 4. Forty-eight Hour Percentage Apoptosis

 


   Discussion
Top
Materials and Methods
 Results
 Discussion
 
Dietary adjuvants to standard cancer therapies have been a focus of investigation in recent years. One such potential agent is emodin, a natural anthraquinone commonly found in the root and stems of rhubarb plants. A common reagent of traditional Chinese herbal treatment, recent studies have begun to investigate its potential clinical applications. Emodin has been postulated to inhibit cellular proliferation through several proposed mechanisms: (1) alterations in the cellular redox state, generating reactive oxygen species that alter mitochondrial membranes, and (2) as a tyrosine kinase inhibitor, able to prevent cell growth by inhibiting the phosphorylation of tyrosine residues on growth factors or signaling molecules. It has also been reported that emodin-induced apoptosis was caused by reactive oxygen species and Bcl-2/Bax–dependent mitochondrial signaling pathway in human lung adenocarcinoma A549 cells.22 However, the antiproliferative effect of emodin has not been evaluated in human pancreatic adenocarcinoma cells, which may upon further study be a potentially synergistic or additive strategy in consolidation therapies using cytotoxic chemotherapy for treating pancreatic cancer.

The present novel results demonstrate that emodin can significantly decrease cellular proliferation, and this effect was observed with 4 distinct pancreatic cell lines. These effects are time- and dose-dependent, with an optimal effect at a concentration of 50 µM. Emodin resulted in proliferation inhibition for Mia Paca-2 cells (Figure 1) in the range of 87%-58% at the various treatment times. L3.6pl cells (Figure 2) showed an 82%-44% decrease in proliferation with 50 µM emodin treatment. Panc-1 cells (Figure 3) treated with 50 µM emodin showed an inhibition of 103%-82%. In BxPc-3 cells (Figure 4), 50 µM emodin inhibited proliferation in the range of 110%-62%. The antiproliferation effects were optimum at a concentration of 50 µM and appear most evident at 48 hours. The viability of pancreatic cancer cells at 72 hours (data not shown) strongly suggests an antiproliferation, not cytotoxic, effect of emodin. To confirm these observations, Western blot analysis for PARP cleavage was performed in Mia Paca-2 cells. PARP cleavage is an early indicator of apoptosis, and the analysis revealed that Mia Paca-2 cells treated with emodin have higher PARP cleavage products than do controls, supporting the induction of apoptosis by emodin rather than toxicity. To clarify our findings, an analysis of PI flow cytometry was performed in 4 cell lines with varying chemoresistance. The strength of chemoresistance is as follows: Panc-1 > Mia Paca > BxPC3 > L3.6pl. As shown above, three-fourths of the cell lines showed a higher apoptotic percentage after emodin treatment.

The Mia Paca-2 cell line was used in this feasibility study for several reasons. Our laboratory has experience using this cell line, and our work as well as the work of others23 has shown it to have a high baseline nuclear factor {kappa}B level (NF{kappa}B). We chose a cell line that has baseline chemoresistance to study its apoptosis induction ability.

In vitro models of pancreatic cancer are available in a multitude of characteristically distinct cell lines. These lines express a multitude of different genes and proteins. Fas-ligand, K-Ras, Cox-2, and NF{kappa}B are a few of the described protein alterations in pancreatic cancer research. Gemcitabine is the primary chemotherapeutic drug in pancreatic cancer. Resistance to gemcitabine is another profile by which the cell lines are characterized. The cell lines used in the present experiments represent a wide range of expression profiles. The Panc-1 and Mia Paca cell line express a relatively high amount of NF{kappa}B, while L3.6pl expression is relatively low. Elevated NF{kappa}B levels have been shown to be at least partially responsible for chemotherapeutic resistance in pancreatic cancer.24 Panc-1 cells are relatively resistant to gemcitabine, while the L3.6pl line is not. In the current studies, the chemosensitive L3.6pl cell line shows a 50% reduction in proliferation at 48 hours, while the gemcitabine-resistant Panc-1 line shows only a 25% reduction. We show that across a spectrum of pancreatic cancer cell line expression profiles, emodin is antiproliferative. A plausible mechanism for its antiproliferation effects is through apoptosis induction, as shown by elevated PARP cleavage.

In summary, these feasibility experiments provide initial evidence that emodin exerts an antiproliferative effect, likely through apoptosis induction–related mechanism(s), that is reproducible in various human pancreatic cancer cell lines, an observation that is consistent with research on other human cancer cells.4,12,13,16,17 However, despite these observations, the actual molecular mechanisms remain to be defined. Future studies to dissect the mechanism(s) of emodin activity are planned, with the focus on cell-cycle progression, progression to apoptosis, and possible chemosensitization with the standard pancreatic cancer chemotherapeutic agent gemcitabine, to evaluate the potential for enhanced chemotherapeutic sensitivity.


  
Top
Materials and Methods
 Results
 Discussion
 
Financial disclosure: none declared.

Received for publication January 29, 2007. Accepted for publication September 28, 2007.

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Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 2, 190-196 (2008)
DOI: 10.1177/0148607108314371
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