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Parthenolide from Parthenium integrifolium reduces tumor burden and alleviate cachexia symptoms in the murine CT-26 model of colorectal carcinoma.

ARTICLE INFO

Keywords: Cancer cachexia

Parthenolide

Parthenium integrifolium

Tumor burden

Skeletal muscle

ABSTRACT

Excessive elaboration of proinflammatory cytokines are involved in cachexia-related hypercatabolism. Parthenolide, as a potential anti-inflammatory active agent, could effectively inhibit nuclear factor-kappa B, and has the potential for the treatment of cancer cachexia. In this study, the cancer cachexia model was established by subcutaneous transplantation CT26 tumor fragment. Parthenolide or placebo was intraperitoneally given daily from the next day. Parthenolide treatment could effectively preserve the body weight, improve the mass of gastrocnemius and tibialis anterior muscles, and alleviate tumor burden. Sizes of muscle fibers and myosin heavy chain were also increasing. The serum proinflammatory cytokine TNF-[alpha] level was lower than placebo treatment mice measure by ELISA. To investigate the possible mechanism, MuRF1 and Fbx32 was subjected to Western blot analysis and expression of MURF1 was inhibited in gastrocnemius muscle. Collectively, parthenolide treatment could effectively alleviate tumor burden of cachexia, preserve the body weight and improve skeletal muscle characteristics.

[c] 2013 Elsevier GmbH. All rights reserved.

Introduction

The high incidence and mortality rates of cancer cachexia attract much attention in recent years (Morley et al. 2006). Evidences show that proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor-[alpha] (TNF-[alpha]), are the common causes of cachexia (Moldawer and Copeland 2000). These cytokines act synergistically to activate nuclear factor kappa B (NF-[kappa]B), resulting in high expression and activation of downstream ubiquitin-mediated proteolytic system (Attaix et al. 2008). These are associated with the increased muscle protein degradation and decreased muscle protein synthesis, which lead to negative energy balance and weight loss. These indicate that the compounds that have the potentials of intervening inflammatory cytokines and the downstream NF-[kappa]B pathway may preserve body weight and are therapeutic options for cancer cachexia.

Data from our own and other labs show that parthenolide (Fig. 1) have the effect for prevention and relief of advanced cancer (Idris et al. 2009; Kreuger et al. 2012). Parthenolide is a biological active natural compound that possess anti-inflammatory and antitumor activity (Yuan et al. 2006). In vitro studies showed that it can alkylate the cysteine residue in IKK (Idris et al. 2009) and p65 subunit (Garcia-Pineres et al. 2001; Saklani et al. 2012), decrease NE-[kappa]B binding activity, and reduce the production of IL-6, and TNF-[alpha] (Li et al. 2009). In vivo studies showed that parthenolide treatment was associated with reducing NE-[kappa]B binding activity and decreasing levels of cytokines (Saadane et al. 2007; Sheehan et al. 2003). All these experiments indicate that parthenolide could decrease NE-[kappa]B binding activity and inhibit inflammatory cytokine production, and thus may reduce tumor burden and alleviate cachexia symptoms. In the present study, we evaluate the effect of parthenolide for the treatment of cancer cachexia in a cancer cachexia model by subcutaneously grafted CT26 tumor fragments into BALB/c mice.

[FIGURE 1 OMITTED]

Materials and methods

Cell

The murine CT26 colon tumor cells were originally purchased from American Type Culture Collection (Rockville, MD, USA). Cell was maintained in Roswell Park Memorial Institute 1640 medium with L-glutamine (Biowest, Nuaille, France), containing 10% fetal bovine serum (Biowest, Nuaille, France) and penicillin-streptomycin (100 U/ml and 100 mg/ml respectively). The cell was cultured in a humidified atmosphere with 5% C[O.sub.2] at 37 [degrees]C.

Cytotoxic effects of parthenolide

The murine C-126 cells (1 x [10.sup.4] per well) were seeded in a ninety-six-well plate overnight. Then they were treated with varying concentrations of parthenolide in serum-free medium for 24 h. Parthenolide (HPLC purity > 98%) was purchased from Feiyu Biological Technology co., Ltd (Nantong, China). It was dissolved in dimethyl sulfoxide (2 mg/ml) as a stock solution. The final concentration of dimethyl sulfoxide was kept at 0.1%. The control cells were treated with vehicle only (0.1% dimethyl sulfoxide). The effect of the parthenolide on CT26 cell viability was determined with a water-soluble MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay in accordance with the manufacturer's instructions (Roche Biosciences, Indianapolis, IN, USA). This assay is based on mitochondrial dehydrogenase activity of respirating viable cells.

Animal model of cancer cachexia

All procedures involving animals and their care in this study were approved by the animal care committee of our institution in accordance with institutional requirement and Chinese government guidelines for animal experiments. Male BALB/c mice were purchased from Shanghai SLAC Laboratory Animal Co. Ltd (Shanghai, China). The mice were kept in conditions of constant temperature and humidity and fed a standard diet and water ad libitum. The murine CT26 tumor model for inducing cachexia in mice was established as previously described (Aulino et al. 2010; Strassmann et al. 1993). Briefly, forty-eight mice (average body weight 21.72g with SD 1.27g) were randomly divided into four groups (twelve animals per group). Other than control group, 200 ml of 026 cell suspension (about 2 x [10.sup.6]/ml in PBS) were injected subcutaneously into the left flanks of BALB/c mice. From the next day twelve mice were given intraperitoneal injection daily with placebo vehicle (200 ml PBS) and these mice were named as CC group. The other twenty-four mice were given 5 mg/kg/d or 25 mg/kg/d body weight of parthenolide (dissolved in PBS), and assigned as PL group or P_H group. The mice of control group were treated equivalently with PBS. The body weights of the mice were measured every day post-tumor implantation, and tumor length and width were measured using a digital caliper once the tumor was palpable. According to our pilot experiments, 20 days after tumor inoculation, mice were euthanised by inhalation of the carbon dioxide. Blood samples were collected into tubes, and serum was separated within 1 h. For the analysis of the effect, tumors removed to calculate the body weight as the whole body weight minus the tumor weight. Epididymal fat and organs were dissect and weighed to compare the weights. Gastrocnemius and tibialis anterior muscles from both legs were also removed, weighed and quickly frozen in liquid nitrogen for biochemical analysis.

Cytokine assays

Total IL-6 and TNF-[alpha] levels in the serum were measured using commercial ELISA kits (Dakewe Biotech Co., Ltd. Shenzhen, China) following the manufacturers' recommended procedure and quantified by detecting absorbance at 450 nm and 630 nm using a BioTek Instruments (Bio-Tek, Winooski, VT). The lowest detectable level of IL-6 and TNF-[alpha] in this assay was 6 pg/ml.

Muscle histology

Transverse serial sections of gastrocnemius and tibialis anterior muscles were fixed with 4% paraformaldehyde in 0.2 M phosphate buffer saline (PBS) for 10 min at room temperature. Then they were washed and stained using hematoxylin and eosin staining (Sigma Chemical Co., St Louis, USA). Images of muscle sections were recorded using a digital camera.

Western blot analysis

Muscle tissues from animals were homogenized and solubilized in lysis buffer (20 mM Tris (pH 7.5), 150 mM NaCl, 1% Triton X-100, sodium pyrophosphate, [beta]-glycerophosphate, [Na.sub.3]V[O.sub.4], EDTA, and leupeptin) using a commercial kit (Beyotime Institute of Biotechnology, China). The detergent-solubilized extracts were centrifuged to remove insoluble matter. After the protein content was evaluated using a bicinchoninic acid Protein Assay Kit (Pierce, Rockford, USA), protein was solubilized in sample loading buffer. For the separation of protein with molecular weight lower than 80 kD, 10% SDS-polyacrylamide gel was used with 30 mg protein sample each lane. The MHC protein (higher than 150 kD in molecular weight) was separated by 6% SDS-polyacrylamide gel. Subsequently proteins were electrophoretically separated and transferred onto PVDF membranes (Millipore Corporation, Bedford, USA) for Western blot analysis. Blots were then incubated with anti-MHC (ab51263, 1:1000, Abcam, Cambridge, USA), anti-MURF1 (ab77577, 1:1000, Abcam, Cambridge, USA) and anti-Fbx32 (ab74023, 1:500, Abcam, Cambridge, USA) primary antibodies according to the manufacturer's specifications. Proteins were detected by chemiluminescence system using a peroxidase-conjugated secondary antibody (1:5000 diluted in Tris-buffered saline with Tween-20). Quantified analysis of the level of protein expression was carried out by Gel-Pro Analyzer program (Media Cybernetics, USA). To verify an equal distribution of protein loading, blots were probed with a peroxidase-conjugated glyceraldehyde-3-phosphate dehydrogenase (GAPDH. 1:1000; Cell Signaling Technology, Beverly, USA) antibody.

Statistical analysis

One-way ANOVA was used for overall comparisons across all treatment groups. Post hoc pairwise comparisons were performed using Tukey's multiple-comparison test. Statistical analysis was completed using IBM SPSS Statistics (IBM Corp., Somers, USA). Data were summarized of treatment group using mean and standard error. A value of p < 0.05 (2-sided) was considered statistically significant.

Results

Anti-cancer of parthenolide

In vitro MTT assay showed that parthenolide reduced viability of CT26 cells in a concentration-dependent manner. IC50 value of parthenolide against CT26 cell was 13.6 [micro]M. In vivo results indicated that tumors were palpable in mice initially around eight days after tumor inoculation. After the tumor volume reached 1.0 [cm.sup.3], the tumors began to grow quickly. The tumor weight (g) was calculated as 0.5 x tumor length x tumor width x tumor width (cm), which was displayed in Fig. 2. On the day 18, the average tumor weight of Control, P_L and P_H group were 2.18, 1.46, and 0.97g respectively, and the difference between groups reached significant level (p < 0.05). After the mice were sacrificed, the tumors were removed and accurately weigh. Compared to CC group (2.98 [+ or -] 0.34g), tumor weigh of PL (2.04 [+ or -] 0.45 g) and P_H (1.48 [+ or -] 0.43 g) group were significantly decreased and this indicated that parthenolide could reduce cancer burden and slowed down the process of cancer cachexia.

[FIGURE 2 OMITTED]

Effect of parthenolide on body and organ weight loss

There was no difference of initial body weights of mice among the four groups before experiment. To evaluate the effect of parthenolide on cachexia. body weight of mice were measure every day after tumors were palpable, as showed in Fig. 3A. The body weights were calculated as the whole mice weight minus tumor weight. From day 8 after tumor inoculated, the tumor-bearing mice began to show ruffled fur, and their activity was decreasing. The body weight of CT26 tumor-bearing mice was declined quickly after day 14. However, in mice treated with low and high dosages of parthenolide, the weight losses were decreased slowly than the placebo-treatment mice. After the mice were sacrificed, the tumors were removed and the accurate body weights were measured, as showed in Fig. 3B. The body weights of placebo-treatment mice were significant lower than control group, indicating that the CT26-tumor bearing mice formed the weight loss characters. Comparing with placebo-treatment mice, parthenolide-treatment resulting in preserving of 8.34% body weight, and there was significant difference of body weight between parthenolide-treatment and placebo-treatment cachexia mice.

[FIGURE 3 OMITTED]

The accumulated food intake was also measured and showed in Fig. 4. Though the daily food intake was decline in a short period of time from day 9 to 12, there was no different of the accumulated food intake of the four groups. These means that administrated of 5 mg/kg/d and 25 mg/d parthenolide had no effects on food intake in this model.

[FIGURE 4 OMITTED]

As can be seen from the results presented in Table 1, cancer cachexia has no effect on the weights of liver and lung. However, the weights of heart and kidney were significant lower than control group. The heart and kidney weight were about 73% and 81% of healthy controls respectively. Parthenolide alleviate the weight loss of heart but showed no alleviated effect on kidney. The spleen weights were almost double in all tumor group, these mean that there was an evident immune and inflammatory responses. Furthermore these organ weight data, without abnormal organ weights, imply that in the mouse cachexia model bearing CT-26 tumor, no obviously toxic was found.
Table 1

Effects of parthenolide on body, organs and skeletal muscles
weights in mice bearing the CT26 tumor.

                         CC          P_L          P_H      Control

Body weight     19.42 [+ or  21.05 [+ or  21.03 [+ or  23.91 [+ or
                    -] 0.27      -] 0.65      -] 0.46      -] 0.46
                        (a)          (b)          (b)

Heart             103.89 [+    111.89 [+    112.30 [+    142.22 [+
                 or -] 5.19   or -] 5.54   or -] 4.69   or -] 4.97
                        (a)     (a), (b)     (a), (b)

Liver            1043.56 [+   1129.00 [+   1099.60 [+   1141.67 [+
                      or -]        or -]        or -]        or -]
                      28.23        35.34        36.83        33.23

Lung              128.67 [+    134.44 [+    134.00 [+    138.89 [+
                 or -] 3.03   or -] 6.14   or -] 6.05   or -] 1.78

Spleen            209.67 [+    215.33 [+    190.10 [+    111.11 [+
                or -] 17.97  or -] 21.48  or -] 20.07   or -] 3.10
                        (a)          (a)          (a)

Kidney            298.11 [+  350.0 [+ or    321.80 [+    367.67 [+
                 or -] 9.26     -] 20.44        or -]        or -]
                        (a)          (b)        14.18        14.70

Epididymal fat    309.11 [+    386.11 [+    350.75 [+    478.22 [+
                      or -]  or -] 44.05        or -]        or -]
                      28.75          (b)        49.60        38.47

Gastrocnemius     222.67 [+    233.22 [+    235.60 [+    261.56 [+
                 or -] 5.84   or -] 6.75   or -] 4.50   or -] 4.76
                        (a)     (a), (b)     (a), (b)

Tibialis        74.78 [+ or  76.78 [+ or  82.40 [+ or  86.33 [+ or
                    -] 2.74      -] 2.40      -] 7.65      -] 2.05
                        (a)                       (b)

Data were shown as mean [+ or -] SD.

(a) Significantly different from control group (p < 0.05).

(b) Significantly different from CC group (p < 0.05).


Fat loss is one important characteristic of cancer cachexia. As previous data showed (Aulino et al. 2010), epididymal fat was loss almost 35%. Comparing with cachexia mice, 5 mg/kg/d parthenolide could effectively alleviate the weight loss epididymal fat by 24.91%.

Parthenolide improves skeletal muscle characteristics

We next examined whether the increase in body weight in tumor-bearing animals on parthenolide treatment was due to improvements in the animals' muscle characteristics. The implantation of the CT26 tumor to mice resulted in significantly loss of gastrocnemius muscles (15%) and tibialis anterior muscles (13%). These results agree with previous studies (Aulino et al. 2010). Table 1 presents the results obtained using two different concentrations of the parthenolide. 5 mg/kg/d and 25 mg/kg/d parthenolide treatment result in significantly amelioration of gastrocnemius muscle loss (p < 0.05). In addition, though no significant increase was found by low concentrations of the parthenolide (5 mg/kg/d) treatment. 25 mg/kg/d could significantly improve the weight of tibialis anterior muscle by 10.2%. The routine hematoxylin and eosin staining results indicated that there was an increased variation in the diameter of fibers and muscle fiber atrophy in cachexia mice. However, compared with cachexia mice, as presented in Fig. 5, mice with low and high dosage of parthenolide-treatment showed an increasing size of gastrocnemius muscle fibers.

[FIGURE 5 OMITTED]

Parthenolide inhibits TNF-[alpha] and IL-6 production

We then compare the expression of cytokines in serum. As shown in Fig. 6, high levels of TNF-[alpha] and IL-6 were detected in the placebo treatment mice. Though parthenolide treatment had no effect on the IL-6 level, the TNF-[alpha] production was significantly inhibited by parthenolide-treatment.

[FIGURE 6 OMITTED]

Parthenolide inhibits proteasome expression in skeletal muscle

Effect of parthenolide on muscle Myosin Heavy Chain (MHC) expression was first compared by Western blot analysis (Fig. 7C). The present results (Fig. 7A) indicate that MHC was significantly higher than the placebo treatment mice. We further investigated whether improvements in muscle characteristics after parthenolide treatment was a result of parthenolide's effects on the proteasome pathway. Activation of the ubiquitin-proteasome pathway plays a major role in the development of muscle atrophy. Of which, muscle RING-finger protein-1 (MURF1) and ubiquitin ligase atrogin-1 F-box (Fbx32) is the two limiting constituents of ubiquitin proteasome system (Bodine et al. 2001: Hobler et al. 1998). We then tested the expression of Fbx32 and MURF1 in gastrocnemius muscles. As shown in Fig. 7B, there was no significant difference between low and high parthenolide treatment in the Fbx32 expression. However, expression of MURF1 was reduced by parthenolide treatment. Moreover, high dosage parthenolide-treatment displayed a significant inhibition of MURF1 expression when compared with cachexia mice, and it was more effective than low dosage of parthenolide. These confirm the effect of parthenolide on muscle and given the possible mechanism that it could reduce the production of TNF-[alpha], and inhibit MURF1 expression. thus improving the expression of MHC.

[FIGURE 7 OMITTED]

Discussion

Our in vitro MTT assays showed that parthenolide possessed the inhibited proliferation of CT26 cells with IC50 13.6 [micro]M (Parada-Turska et al. 2007). Previous in vivo studies had demonstrated parthenolide's anti-tumor and antiinflammatory activity (Shanmugam et al. 2006; Shanmugam et al. 2010; Smolinski and Pestka 2003). Its pharmacological mechanism is correlated with its ability of inactivation of IKK[beta] (Hehner et al. 1999) and NF-KB (Liu et al. 2009). Studies showed that increasing levels of IL-6 and TNF-[alpha] is correlated with the development of cachexia (Argiles et al. 2006; Iwase et al. 2004; Strassmann et al. 1992). These cytokines would activate IKK complex, leads to the release of NF-KB, and subsequently binding to DNA, resulting in activation of the proteolytic ubiquitin proteasome system and the breakdown of skeletal muscle (Murphy and Lynch 2009; Reid and Li 2001). It is interesting to note that intervention of proinflammatory cytokine is proved to be a beneficial treatment strategy for cachexia (Argiles et al. 2006, 2011).

To get the right dosage of parthenolide for the in vivo experiment, we had referred previous research (Curry et al. 2004; Sweeney et al. 2005). Moreover our preliminary study had tested the safety and tolerability of parthenolide in male BALB/c mice, and found that there was no obviously toxic when the dosage of parthenolide was up to 25 mg/kg/d. So in the model of cachexia inducing by CT26 tumor, the dosages of parthenolide was determined as 5 and 25 mg/kg/d and its effect was researched. High and low dosage of parthenolide resulted in weight gains compared with that of placebo-treated animals despite the presence of tumor. It is noticeable that tumor burden of parthenolide-treated mice were significant lower than placebo-treated animals. Therefore, parthenolide could effectively reduced tumor burdens. These results are obvious in Fig. 3. During the clay from 14 to 16, the tumor growth rate of parthenolide-treated mice was significant slower than placebo-treated animals. These data agreed with the body weight. From day 14 to 18, the body weights of parthenolide-treated mice were decreasing slower than placebo-treated animals. Another interesting effect of parthenolide was that the body-weight gain was independent of food intake as there was no difference between the food intake of control and parthenolide-treated animals.

Furthermore, the effects of parthenolide treatment on alleviating cachexia symptoms in CT26 tumor-bearing mice are also evident by the facts of weight gain in gasctrocnemic muscle (4.7% and 5.8%) and tibialis anterior muscle (2.7% and 10.2%), and increased size of muscle fibers. Moreover, the MHC of skeletal muscle was altered in model mice (Diffee et al. 2002). The MHC expression from Western blot analysis revealed that the parthenolide treatment could restore the MHC content. To evaluate the effect of parthenolide on the proinflammatory cytokine and the downstream proteolytic ubiquitin proteasome system, we first measured the levels of IL-6 and TNF-[alpha]. Data showed that parthenolide treatment resulted in the low expression of TNF-[alpha] in the mice serum. The two limiting constituents of ubiquitin proteasome system, Fbx32 and MURF1, were also measured by Western blot analysis. Though no difference of Fbx32 expression was found. MURF1 expressions in gastrocnemius muscles from parthenolide-treated mice are obviously lower than placebo-treated mice. All these results confirm that in CT26 tumor inducing cachexia model, parthenolide treatment could effectively reduce tumor burden of cachexia, preserve the body weight, and improve skeletal muscle characteristics.

Acknowledgements

The present study was supported by a grant from Polytechnic crossing project, Shanghai Jiaotong University. The authors wish Co thank Yali Li and Yao Fu for the help of animal care.

* Corresponding author at: Shanghai Sixth People's Hospital, Shanghai Jiaotong University. Building 11, No. 600. Road Yishan, Shanghai 200233, PR China.

Tel.: +8621 24058098.

E-mail address: guoc66@gmail.com (G. Cheng).

0944-7113/$--see front matter [c] 2013 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2013.04.020

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(1.) These authors contributed equally to this work.

Yang Quanjun (a), (b), (1), Wan Lili (a), (1), Zhou Zhiyong (a), (b), Li Yana, Yu Qi (a), Liu Liya (a), (c), Li bin (a), (c), Guo Cheng (a), (b), *

(a) Department of Pharmacy, Shanghai Sixth People's Hospital. Shanghai Jiaotong University, Shanghai 200233, PR China

(b) School of Shanghai Jiaotong University. Shanghai 200240, PR China

(c) Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
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Author:Quanjun, Yang; Lili, Wan; Zhiyong, Zhou; Yan, Li; Qi, Yu; Liya, Liu; bin, Li; Cheng, Guo
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9CHIN
Date:Aug 15, 2013
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