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Diallyl trisulfide (DATS) inhibits mouse colon tumor in mouse CT-26 cells allograft model in vivo.

ARTICLE INFO

Keywords: Diallyltrisulfide(DATS)

Mouse colon tumor

Mouse CT-26 cells

Allograft model

In vivo

ABSTRACT

Our earlier studies showed that DATS induced apoptosis in human colon cancer HT29 and colo 205 cell lines in vitro. However, there is no report to show that DATS induced apoptosis in vitro and inhibited CT26 cancer cells in vivo on a murine allograft animal model. In vitro studies, the results indicated that DATS induced morphological changes and induction of apoptosis in CT26 cells. In vivo studies, CT26 cancer cells were implanted into BALB/c mice and groups of mice were treated with vehicle, DATS (10 and 50 mg/kg of body weight). DATS were injected once per four days intraperitoneally (Lp-), with treatment starting 4 weeks prior to cells inoculation. Treatment with vehicle or with 10 and 50 mg/kg of DATS resulted in a reduction in tumor volume and weight. Tumor volume and total hemoglobin in allograft mice treated with 50 mg/kg DATS were significantly smaller than that in the control group. These findings indicated that DATS inhibits tumor growth in an allograft animal model. Thus, DATS may represent a colon cancer preventive agent and can be used in the future.

[c] 2011 Elsevier GmbH. All rights reserved.

Introduction

Numerous studies have shown that dietary intakes of Allium vegetables (e.g., garlic) may reduce the risk of different types of malignancies including stomach, esophageal, and prostate cancer (Gao et al. 1999; Hsing et al. 2002; You et al. 1989). It was reported that the anticarcinogenic effect of Allium vegetables is attributed to organosulfur compounds (OSCs) (Powolny and Singh 2008), including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), and have demonstrated anti-cancer activities in animal models induced by a variety of chemical carcinogens (Hong et al. 1992; Reddy et al. 1993; Sparnins et a1.1988; Wargovich et al. 1988). The mechanisms of those compounds to inhibit chemically induced cancer have been shown to involve an increase in expression of glutathione transferases and quinone reductase and/or inhibition of cytochrome P450-dependent monooxygenases (Brady et al. 1991; Herman-Antosiewicz et al. 2007a; Herman-Antosiewicz and Singh 2004; Hu et al. 1996; Singh et al. 1998). Several studies from Dr. Singh's laboratory have demonstrated that DATS was a much more potent suppressor of cancer cell proliferation compared with either DAS or DADS by using human prostate and lung cancer cells (Xiao et al. 2004, 2005).

Several reports have indicated that the DATS-mediated apoptosis in cancer cells via the generation of reactive oxygen species (ROS) and regulation by activation of c-jun N-terminal kinases and induction of Bax/Bak (Kim et al. 2007; Xiao et al. 2004, 2009a) and the generation of ROS is accomplished by an increase in labile iron pool due to proteasome-mediated degradation of iron storage protein ferritin (Antosiewicz et al. 2006).

It was also reported that tDATS activated mitotic arrest in human prostate cancer cells lacking functional p53 (PC-3 and DU145) in association with activation of checkpoint kinase 1 (Chkl) (Herman-Antosiewicz and Singh 2005; Herman-Antosiewicz et al. 2007b). Recently, Singh et al. also reported that Chkl dependence of DATS-induced mitotic arrest in human cancer cells is not influenced by the p53 status and cells arrested in mitosis upon DATS exposure are driven to apoptotic DNA fragmentation (Xiao et al. 2009b).

It was reported that DATS-mediated inhibition of PC-3 human prostate cancer xenograft growth in vivo is accompanied by induction of Bax and Bak (Xiao et al. 2006). Furthermore, oral treatment of DATS inhibited incidence and burden of poorly differentiated carcinoma and pulmonary metastasis multiplicity in a transgenic mouse model of prostate cancer without causing any harmful side effects (Singh et al. 2008). However, there is no report to show that oral treatment of DATS affected CT26 mouse colon cancer allograft growth in vivo. Thus, in the present study, we use mouse cancer cells to generate CT26 mouse colon cancer allograft before treating with oral DATS to examine whether or not DATS decreased the tumor size in vivo.

Materials and methods

Chemicals

Diallyl trisulfide (DATS), dimethyl sulfoxide (DMSO), propidium iodide (PI), Triton X-100 and trypan blue were obtained from Sigma Chemical. (St. Louis, MO, USA).

Cell culture

Mouse colon carcinoma CT26 cells were obtained from the Food Industry Research and Development Institute (Hsinchu, Taiwan) and were maintained at 37[degrees]C in a humidified 5% [C.sub.2] and 95% air, with RPMI-1640 medium (Gibco-BRL, Grand Island, NY, USA) supplemented with 10% FBS (Hyclone Laboratories, Logan, UT, USA), 1% penicillin-streptomycin (100 units/ml penicillin and 100mg/ml streptomycin) and 1% glutamine.

Assessment of cell morphology and viability ofCT26 cells after exposed to DATS

A total of 2 X [10.sup.5] cells/well of CT26 cells were cultured in 12-well plates and incubated at 37[degrees]C for 24 h before each well were treated with 0, 5, 10, 20 and 40[micro]p,M DATS for 24, 48 and 72 h. DMSO (solvent for DATS) was used for the control regimen. For cell morphological changes experiment, the cells in each well of plate were examined under a phase-contrast microscope and then were photographed (Ho et al. 2009b; Lu et al. 2010). For cell viability experiment, the cells were harvested from above and each treatment then analyzed by flow cytometric protocol as previously described (Chen et al. 2010; Lu et al. 2010).

Determination sub-G1 phase (apoptosis) by flow cytometry

Approximately 2 X [10.sup.5] cells/well of CT26 cells were cultured in 12-well plates and incubated at 37[degrees]C for 24 h before each well was treated with 0, 5, 10, 20 and 40[micro]M DATS for 48 h. DMSO (solvent for DATS) was used for the control regimen. At the end of treatment, adherent cells were trypsinized, combined with nonadherent cells, collected by centrifugation for 5 min at4':[degrees]C, at 1000 rpm then washed twice with ice-cold PBS and then fixed in ice-cold 80% ethanol overnight at -20[degrees]C. Next, cells were centrifuged for 5 min at 4[degrees]C, at 1000 rpm, washed twice with PBS and re-suspended in 1 ml of DNA staining solution (20mg/ml of propidium iodide (PI) and 100 mg/ml of RNase A in PBS), for 30min in the dark. Flow cytometric analyses were performed using a FACScan cytometer (Becton Dickinson, San Jose, CA, USA) (Augustin et al. 2010; Yang et al. 2010). All experiments were performed at least three times.

Mouse allograft tumor model

Thirty six-week-old female BALB/c mice were purchased from Laboratory Animal Center, College of Medicine, National Taiwan University (Taipei, Taiwan). All experimental procedures were performed in accordance with the protocols approved by the Animal Care and Use Committee of China Medical University (Taichung, Taiwan). Mice were maintained in a standard vinyl cages with air filter tops and in a filtered laminar air flow room, and water and food were autoclaved and provided ad libitum. Overall, the whole experimental design is shown in Fig. 1.

To develop the CT26 allograft, CT26 cells (1 X [10.sup.6]) in PBS underwent intraperitoneal (i.p.) injection into mice. Animals bearing tumors were randomly assigned to treatment groups (ten mice per group) and treatment imitated and oral (p.o.) gavage every four days (in the morning) with control vehicle (olive oil), DATS (10mg/kg), DATS (50mg/kg) (Chou et al. 2009; Kim et al. 2010). Mice exhibiting tumors from each group were monitored, counted, and the tumor sizes were measured initially after tumor cell inoculation. Body weight from each animal was measured at least once per four days but more frequently measured. At the end of the study (32 days after cell inoculation), animals were sacrificed. Tumors were removed, measured and weighted individually. Tumor volume was calculated by using mean diameter measured with Vernier calipers and using the formula volume [(mm.sup.3]) v =0.5 X a X [b.sup.2], where a and b are the smallest and the largest diameter, respectively (Chou et al. 2009; Jones-Bolin et al. 2006).

Hemoglobin assay in vivo

Tumors from each animal of control and DATS treatment were removed, hemoglobin was measured as an indication of blood vessel formation, using the Drabkin method (Drabkin reagent kit 525; Sigma-Aldrich, St. Louis, MO) (Tsai et al. 2010). The concentration of hemoglobin from each treatment was calculated based on a known amount of hemoglobin assayed in parallel.

Statistical analysis

Each value represents mean[+ or -]S.D., and the treated-groups and control were compared by Student's t-test. *** p < 0.001 was considered significant.

Results

DATS affected the morphological changes and percentage of viable CT26 cells in vitro

The growth of the mouse colon cancer CT26 cells in the presence of various concentrations of DATS ranging from 5 to 40[micro]M was determined by morphological changes and by using flow cytometry, and the results are shown in Fig. 2A and B. After a continuous 72 h exposure, DATS significantly induced morphological changes, mainly changing the cell shape from spinal to round (Fig. 2A). The round-shaped cells mean dead cells initiated by DATS. The results from Fig, 2B indicated that DATS induced a significant decrease in the cell viability and these effects are in a concentration- and time-dependent manner (Fig. 2B).

DATS induced apoptosis in CT26 cells in vitro

[FIGURE 1 OMITTED]

The effect of the DATS on sub-Gl of cell cycle progression of mouse colon cancer cells was determined by flow cytometry. The cell sub-Gl occurs were accompanied by a dose-dependent of DATS appearance of typical for late stage of apoptosis, sub-Gl peak (4-48% of apoptosis from 5 to 40[micro]M DATS treatment). The incubation of CT26 cells with higher DATS concentration (40[micro]M) significantly increased the percentage of sub-Gl cells (up to 48% after 48 h, Fig. 3).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

DATS affected the body and tumor weights of CT26 tumor allograft mice in vivo

The therapeutic efficacy of DATS was compared to that of vehicle (control) in a CT26 allograft tumor model in mice. DATS was administered by intraperitoneal (i.p.) injection and then all animals were monitored and weighed as described in Methods section. Groups of mice were treated with DATS (l0mg/kg), DATS (50mg/kg) and control with DMSO, and the treatments of DATS at a higher concen- tration (50 mg/kg) increased body weight significantly compared to control (Fig. 4A). DATS at higher concentration (50mg/kg) also decreased significantly the tumor volume compared to control (Fig. 4B) and the representative tumor and percentages of inhibition of tumor are shown in Fig. 4C.The results indicated that DATS induced 34% inhibition of tumor weight compared to control. With regard to tumor mass, tumor growth seemed to decrease in the DATS groups compared to control group. Tumors in the treatment groups were significantly smaller than that in the control group.

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

DATS affected the hemoglobin of CT26 tumor allograft mice in vivo

In order to know whether DATS affect hemoglobin levels in CT26 tumor allograft mice, we investigated and determined the concentration of hemoglobin in transplantation tumors from tumor tissue and the results are shown in Fig. 5, which indicated that the levels of hemoglobin from tumor sections significantly decreased in DATS (50mg/kg) treated-CT26 allograft mice as compared with control group. The results suggest that DATS may cause anti-tumor and anti-angiogenesis activities in CT26 allograft animal model in vivo.

Discussion

Numerous studies have shown that DATS induced cytotoxic effects through the cell cycle arrest and induction of apoptosis in many cancer cell lines (Hosono et al. 2005; Kim et al. 2008; Sparnins et al. 1988; Wargovich et al. 1988; Xiao et al. 2006), but no reports show that DATS affected mouse colon cancer CT26 cells in allograft mouse in vivo. In the present study, we provide the first in vivo evidence for the efficacy of DATS on mouse colon cancer CT26 tumors in mice.The entire experiments were divided into in vitro and in vivo experiments. In the in vitro studies, the aim of the current study was to investigate and characterize the cellular response of mouse colon cancer CT26 cells to DATS treatment. The inhibition of tumor cells growth seems to be the first effect of action of anti-cancer drugs, including DATS. The other cellular effects including apoptosis, necrosis or senescence occur with some delay in relation to inhibition of cell number. Therefore, it was very important to perform all experiments at biologically relevant concentrations of the drug. Mouse colon cancer CT26 cell line was used in this work and DATS exhibited potent antitumor activity against colon cancer CT26 allografts in mice (Hosono et al. 2005).

Cell cycle analysis from DATS treated CT26 cells showed time and dose-dependent appearance of sub-Gl population of CT26 cells, considered as apoptotic. Apoptosis is characterized by several biochemical criteria, including changes in mitochondrial membrane permeability, caspase activation, internucleosomal DNA cleavage, release of intermembrane space mitochondrial proteins in the formation of apoptotic bodies, chromatin fragmentation, shrinkage of cells and bleb formation (Kim et al. 2010; Yang et al. 2010). Therefore, the induction of apoptosis may lead to the reduction of tumor volume in vivo. In the present study the induction of apoptosis by DATS in mouse colon cancer CT26 cells was confirmed by morphological examination and sub-Gl phase of cell cycle distribution of the cells. Cellular morphology and sub-Gl of CT26 cells progressively changed with the increasing duration of DATS exposure (Fig. 3).These morphological observations together with the appearance of sub-Gl populations confirmed the presence of considerable amount of apoptotic CT26 cells.

There are several interesting findings from our in vivo study. First, DATS, at 50 mg/kg could inhibit tumor growth in an allograft mice model. These findings are slightly different from in vitro studies where a similar concentration of DATS (40 fxM) had significant cytotoxic effects on the cellular proliferation (Fig. 2) of CT26 cells and induced apoptosis (Ho et al. 2009a). However, tumors in mice that received DATS alone were about 34% smaller than those of the control group (Fig. 4C). There are no toxic effects at the doses administered of DATS, as evidenced by no changes in body weight or grooming habits compared to normal animal (Wu et al. 2001, 2002). Hence, the growth inhibitory effect of DATS on CT26 allografts in vivo was reflective of the results obtained in vitro. Our results also showed that DATS significantly decreased the levels of hemoglobin in tumor tissues and this may indicate that DATS inhibited the angiogenesis in vivo.

Tumors that received DATS treatment continued to grow slowly, indicating that complete regression of CT26 cells allografts was not achieved using a single treatment. This indicated that multiple treatments may be necessary to achieve complete responses. The reason for the discrepancy between the in vivo and in vitro results may be due to the presence of different metabolites formed in vivo than that is in vitro. This may reflect pharmacokinetic and/or pharmacodynamic interactions involved in DATS decrease the growth of CT26 cells tumors. This finding represents the first study examining the effect of DATS as a colon cancer preventive agent in a colon cancer murine allograft model.

Acknowledgement

This work was supported by the grant NSC 97-2320-B-039-017-MY3 from the National Science Council, Taiwan, R.O.C. and in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004).

0944-7113/$ - see front matter[c] 2011 Elsevier GmbH. All rights reserved.

doi: 10.1016/j.phymed.2011.01.006

* Corresponding author at: Department of Pharmacology, China Medical University, No. 91. Hsueh-Shih Road, Taichung 40402, Taiwan. Tel.: +886 4 2205 2121x7730; fax: +886 4 2205 3764.

** Corresponding author at: Department of Biological Science and Technology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan. Tel.: +886 4 2205 3366x2500; fax: +886 4 2205 3764.

E-mail addresses: jaising@rnail.cmu.edu.tw (J.-S. Yang), (J.-G. Chung)

(1) These authors contributed equally.

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Ping-Ping Wu (a), Kuo-Ching Liu (b), Wen-Wen Huang (c), Fu-Shin Chueh (d), Yang-Ching Ko (e), (f), Tsan-Hung Chiu (g), Jing-Pin Lin (h), Jehn-Hwa Kuo (i), (j), Jai-Sing Yang (k), *, (1), Jing-Gung Chung (c), (1), *

(a) School of Pharmacy. China Medical University, Taichung 404, Taiwan

(b) Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan

(c) Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan

(d) Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan

(e) Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, St Martin De Porres Hospital, Chiayi 600, Taiwan

(f) Department of Nursing, Chungjen College of Nursing, Health Sciences and Management, Chiayi 622, Taiwan

(g) Department of Obstetrics & Gynecology, China Medical University Hospital, Taichung 404, Taiwan

(h) School of Chinese Medicine, China Medical University. Taichung 404, Taiwan

(i) Special Class of Healthcare, Industry Management, Central Taiwan University of Science & Technology, Taichung 406, Taiwan

(j) Department of Urology, Jen-Ai Hospital. Tali, Taichung 412, Taiwan

(k) Department of Pharmacology. China Medical University, Taichung 404, Taiwan

(l) Department of Biotechnology, Asia University, Taichung 413, Taiwan
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Author:Wu, Ping-Ping; Liu, Kuo-Ching; Huang, Wen-Wen; Chueh, Fu-Shin; Ko, Yang-Ching; Chiu, Tsan-Hung; Lin,
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9TAIW
Date:Jun 15, 2011
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