Particled Mica, STB-HO has chemopreventive potential via G1 arrest, and inhibition of proliferation and vascular endothelial growth factor receptor 2 in HCT colorectal cancer cells
- Sung-Yun Cho†1,
- Hyo-Jeong Lee†1,
- Sun-Mi Cho1,
- Bonglee Kim1,
- Yeon Kwon Jung2 and
- Sung-Hoon Kim1Email author
© Cho et al.; licensee BioMed Central Ltd. 2013
Received: 20 December 2012
Accepted: 9 July 2013
Published: 24 July 2013
Though Mica, a thin and sheet like mineral, has been used as a mineral medicine for treatment of bleeding, dysentery and inflammation in traditional medicine including Ayurveda, the biological evidences of Mica were not clearly elucidated so far. Thus, in the present study, the antitumor mechanism of particled Mica (STB-HO) was examined in colorectal cancers.
Athymic nude mice were inoculated with HCT116 colon cancer cells and orally administered STB-HO daily for 41 days, and HCT116 and human umbilical vein endothelial cells (HUVECs) were treated with STB-HO for 0 ~ 24 hours to perform immunoblotting, cytotoxicity assay, FACs analysis and measurement of matrix metalloproteinase 9 (MMP-9) secretion and other experiments. Significant differences of all date were evaluated using Student’s t-test and a Turkey-Kramer multiple-comparison post test.
STB-HO significantly suppressed the tumor volume and weight in athymic nude mice inoculated with HCT116 cells at a dose of 100 mg/kg. Thus, the in vivo antitumor mechanism of STB-HO was to elucidated in vitro as well. STB-HO exerted cytotoxicity in HCT116, SW620 and HCT15 colorectal cancer cells. Also, STB-HO increased G1 cell population in a time and concentration dependent manner, enhanced the expression of p21, p27, p53 as cyclin dependent kinase (CDK) inhibitors, attenuated the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and also reduced the production of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) in HCT116 cells. Consistently, STB-HO suppressed the phosphorylation of VEGFR2 in HCT116, SW620 and HCT15 cells. Also, STB-HO inhibited the VEGF mediated proliferation and also attenuated the phosphorylation of VEGFR2 and Akt in human umbilical vein endothelial cells (HUVECs).
Collectively, these findings suggest that STB-HO has chemopreventive potential via G1 arrest and inhibition of proliferation and VEGFR2 in HCT116 colorectal cancer cells.
KeywordsMica VEGFR Colon cancer G1 arrest Cell proliferation
Colorectal cancer (CRC) is one of the leading causes of mortality in the western world. Chemotherapy including 5-fluorouracil (5-FU) therapy and surgical resection are well known methods for colon cancer treatment . However, the side effects are induced by chemotherapy such as oral mucositis, diarrhea, neuropathy, anemia and alopecia . Thus, recently natural products  and compounds [4–6] were reported to have antitumor effects in colorectal cancers alone or in combination with anticancer agents  with low toxicity. Also, Hu et al. suggested that among men and women taking vitamin and mineral supplements for more than 5 years, significant inverse associations with colon cancer were most pronounced among women with distal colon cancer . Similarly, there are evidences that mineral selenium has antitumor activity in colon cancers [9–12].
The Mica group of sheet silicate minerals are generally classified as trioctahedral Mica including Biotite, Lepidolite, Muscovite, Phlogopite, Zinnwaldite and interlayer deficient Mica. Mica has been used for decoration and treatment for bleeding, dysentery and inflammation in traditional medicine including Ayurveda for ages. Nasrin et al. showed no toxicity of Chondrokola Rosh, a traditional metallic Ayurvedic preparation, including various roasted metals (Hg and Cu), non-metal (sulphur and Mica) and medicinal herbs . Also Mica was known to protect gastric mucosa by improving blood flow and inflammatory response  as well as suppress gastric cancer via regulation of p16 and Bcl-2 in rats , indicating Mica can be used as a medicine . Thus, in the present study, antitumor mechanism of particled Mica (STB-HO) was examined in vitro in HCT116 colorectal cancer and human umbilical vein endothelial cells (HUVECs) and athymic nude mice inoculated with HCT116 cells.
Chemicals and reagents
STB-HO (particled Mica; Korea Patent Registration; 10–0454200) was supplied from Seobong Biobestech Company (Seoul, Republic of Korea). SW620, HCT116 and HCT15 human colorectal adenocarcinoma cells from the American Type Culture Collection (ATCC, Manassas, VA, USA) were maintained in RPMI 1640 supplemented with fetal bovine serum (FBS), liquid gentamicin reagent solution, penicillin and streptomycin (PEST), and trypsin EDTA were purchased from Gibco (Carlsbad, CA, USA). Human umbilical vein endothelial cells (HUVECs) cells from the American Type Culture Collection (Manassas, VA, USA) were maintained in M199 supplemented with 20% fetal bovine serum (FBS), liquid gentamicin reagent solution, penicillin and streptomycin (PEST), 3 ng/ml bFGF, 5 units/ml heparin. Enhanced chemiluminescence (ECL) Western blotting detection reagents and Hyperfilm ECL were from Amersham-Pharmacia Korea (Seoul, Korea). Anti-rabbit IgG heavy and light chain-specific (rabbit, mouse) peroxidase conjugates and antibody against p21, p27, p53, pp53, cyclin D1, pAKT, AKT, PI3K and PCNA were purchased from Cell signaling technology (Denver, MA, USA). Antibodies of VEGFR2 and pVEGFR2 were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). β-actin was purchased from Sigma Chemical Co. (St. Louis, MO, USA). VEGF and MMP-9 ELISA kit were purchased from Invitrogen (Carlsbad, CA, USA). Human recombinant VEGF was purchased from R&D systems (Minneapolis, MN, USA). Cell Proliferation ELISA kit was purchased from ROCHE (F. Hoffmann-La Roche Ltd, Switzerland). All other reagents used were purchased from Sigma Chemical (St Louis, MO, USA).
SW620(ATCC CCL-227™), HCT116(ATCC CCL-247™) and HCT15 cells(ATCC CCL-225™) were seeded onto 100 mm Falcon plates at 2 × 106 cells/mL in RPMI 1640 supplemented with 10% FBS and 1% penicillin/streptomycin. The cells were cultured at 37°C in a humidified atmosphere containing 5% CO2 to 60–80% confluence and then used for Western blot analysis. STB-HO was treated to various human colon cancer cells for 24, 48, 72 and 96 h. HUVECs were maintained in M199 plus 20% heat-inactivated fetal bovine serum (FBS), 3 ng/ml bFGF, 5units/ml heparin, 100 units/ml antibiotic-antimycotic solution (complete M199) in 0.1% gelatin coated flasks and incubated at 37°C in a humidified atmosphere containing 5% CO2. Once confluent, the cells were detached by trypsin-EDTA solution and used in experiments from the third to the sixth passages.
Cell proliferation in HCT116 cells with STB-HO was evaluated as described by using Cell proliferation ELISA kit (Roche, Swiss) according to the manufacturer’s instructions. Briefly, after 48 h treatment of STB-HO, the cells were added by 10 μl/well of bromodeoxyuridine (BrdU) solution and reincubated for 2 h at 37°C. Then, BrdU solution was removed and 200 μl of FixDenat was added to each well. After incubation for 30 min at room temperature, FixDenat solution was removed and 100 μl of anti-BrdU-POD working solution was added to each well. After washing with PBS three times, 100 μl of substrate solution was added to each well and the optical density was measured at 450 nm using microplate reader (Molecular Devices Co., Sunnyvale, CA, USA). All samples were prepared in triplicates and the assay was repeated at least three times.
Cell cycle analysis
HCT116 cells were treated with STB-HO (250 and 500 μg/ml) for 24, 48 and 72 h. The cells were fixed in 75% ethanol at -20°C and treated with RNase A (10 mg/ml) for 1 h at 37°C, stained with propidium iodide (PI) (50 μg/ml) and analyzed for the DNA content by FACSCalibur (Becton–Dickinson, Franklin Lakes, NJ, USA) using CellQuest Software (BD Bio-sciences, San Jose, CA, USA).
Cells (5×106 cells) treated with STB-HO were lyzed by using lysis buffer (50 mM Tris–HCl, pH 7.4, 300 mM NaCl, 0.5% Triton X-100, 0.1% SDS, 5 mM EDTA, and protease inhibitor cocktail). The extracts were incubated on ice for 30 min, and then centrifuged at 13,000×g for 30 min at 4°C and the supernatants were collected for western blotting. Protein concentrations were determined by Bradford assay (Bio-Rad), and equal amounts of proteins (30 μg) were separated by electrophoresis sodium dodesyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to PVDF membranes (Amersham Biosciences, Piscataway, NJ, USA). The membranes were blocked with 5% skim milk in Tris-buffered saline containing 0.1% Tween 20 for 2 h at room temperature. The membranes were probed overnight at 4°C with mouse anti-human β-actin (1:1000; Sigma Aldrich, St. Louis, MO, USA), anti-human pAKT, AKT, p21, p27, p53, pp53, cyclin D1, PCNA and PI3K (1:1000; Cell signaling, Danvers, MA, USA), anti-human VEGFR2 and pVEGFR2 (1:500; Santa Cruz Biotechnology, CA, USA) followed by washing and incubation with HRP conjugated secondary antibody (AbD Serotec, Raleigh, NC, USA). Immunoreactive bands were visualized using the ECL system (Amersham-Pharmacia, Seoul, Korea).
Measurement of VEGF and MMP-9 production by ELISA
VEGF and MMP-9 levels in HCT116 cells treated with STB-HO were measured using VEGF and MMP-9 ELISA kit (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions. Briefly, the culture supernatants was added onto a 96-well microplate, and incubated for 2 h at room temperature. The plate was then washed four times with washing buffer and 100 μl of biotin conjugate was placed to each well for 1 h at room temperature. After washing four times with washing buffer, 100 μl of the stabilized chromogen was placed to each well and incubated for 30 min at room temperature in dark. Finally, 100 μl of stop solution was added to each well and the optical density was measured at 450 nm using microplate reader (Molecular Devices Co., Sunnyvale, CA, USA).
HCT116 xenograft model
Four-week-old female BALB/c athymic nude mice (18 ± 3 g) were purchased from Chung-Ang Laboratory Animals (Seoul, Korea) and housed in animal facility at 22 ± 3°C and 60 ± 10% humidity with light-controlled (12 h, 07:00–19:00) environment. All materials including bedding and feed were sterilely cleaned by UV rays for 30 min before treatment to the mice. The animal study was conducted under the guidelines approved by Institutional Animal Care and use Committee, Kyung Hee University [KHUASP(SE)-11-005] as previously described with minor modifications . Briefly, 2 × 10 6 of HCT116 cells were mixed with Matrigel (Becton Dickinson, 50% in 100 μl) and injected subcutaneously into the right flank of 6-week-old male BALB/c athymic nude mice (Chung-Ang Laboratory Animals, Seoul, Korea)) for 3 groups (Control and two STB-HO treated groups). After 1 week adaptation, the animals were assigned to four groups (n = 6): negative control (vehicle (saline) + HCT116 inoculation), STB-HO50 (50 mg/kg+ HCT116 inoculation), and STB-HO100 (100 mg/kg+ HCT116 inoculation). Everyday STB-HO dissolved in saline was orally treated to the athymic nude mice for 41 days during experiment period. Tumor size was monitored twice a week with a caliper, and tumor volume was also calculated as described . At the end of animal study, tumors were dissected, weighed and photographed.
Data were shown as means ± SE. Significant differences were evaluated using Student’s t-test and a Turkey-Kramer multiple-comparison post test.
STB-HO suppresses tumor growth in HCT116 xenograft model
STB-HO inhibits cell proliferation in human colorectal cancer cell lines
STB-HO induces G1 arrest in HCT116 colorectal cancer cells
STB-HO suppresses the production of VEGF and MMP-9 in HCT 116 colorectal cancer cells
STB-HO suppresses VEGFR2 and PI3K/Akt signaling in colorectal cancer cells
STB-HO inhibits VEGF mediated proliferation and phosphorylation of VEGFR2 and Akt in HUVECs
There are evidences that minerals have antitumor activity in several cancers. For instances, arsenic trioxide (As2O3) was known to treat breast cancer  and colon cancer cells [23, 24], selenium (Se) was reported to have antitumor potential in several cancers such as colon [25, 26], prostate [27, 28], zinc (Zn) was reported to have potential therapeutic for chemoresistant ovarian cancer  and also cadmium (Cd) induced mitogenic signaling in breast cancer cell by an ER alpha-dependent mechanism . Similarly, in the present study, mineral Mica (STB-HO) showed antitumor potential in colorectal cancers. Though STB-HO exerted anti-proliferative activity in HCT116, SW620 and HCT15 colorectal cancer cells, HCT116 cells are were more susceptible to STB-HO compared to two other colon cancer cells, since they are positive for transforming growth factor beta 1 (TGF beta 1) and beta 2 (TGF beta 2) expression with a mutation in codon 13 of the ras protooncogene .
Also, STB-HO increased G1 cell population in a time and concentration dependent manner and enhanced the expression of p21, p27, p53 as cyclin dependent kinase (CDK) inhibitors [32–34], attenuated the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1, implying G1 arrest leading to cell death by STB-HO in HCT116 cells. Furthermore, STB-HO attenuated the expression of survival gene PCNA and reduced typical angiogenesis marker VEGF production in HCT116 cells, indicating anti-proliferative and anti-angiogenic activity of STB-HO in HCT116 cells.
VEGF is an important signaling protein involved in both vasculogenesis and angiogenesis. As an essential receptor protein tyrosine kinase propagating cellular signal transduction processes, VEGFR-2 is a central target for drug discovery against tumor-associated angiogenesis . Consistently, STB-HO suppressed the phosphorylation of VEGFR2 in HCT116, SW620 and HCT15 cells and also inhibited the VEGF mediated proliferation as well as attenuated the phosphorylation of VEGFR2 and Akt in human umbilical vein endothelial cells (HUVECs), strongly demonstrating anti-angiogenic activity via inhibition of VEGFR2 signaling. Consistently, ELISA revealed that STB-HO reduced the production of VEGF and MMP-9 in HCT116 cells. Nevertheless, it was noteworthy that STB-HO suppressed the tumor volume and weight in athymic nude mice inoculated with HCT116 cells at a dose of 50 and 100 mg/kg through two animal studies. However, the in vitro effective concentration was high because of poor solubility of STB-HO in cell culture study, which should be improved by nanoparticle method, synthesis or new dilution methods in the near future.
Mineral Mica (STB-HO) showed cytotoxicity in colorectal cancer cells, increased G1 arrest and, reduced VEGF production in HCT116 colorectal cancer cells, attenuated the phosphorylation of VEGFR2 and Akt in HUVECs and suppressed the tumor volume and weight in athymic nude mice inoculated with HCT116 cells. Collectively, these findings suggest that STB-HO has chemoprevntive potential via G1 arrest and inhibition of proliferation and VEGFR2 in HCT116 colorectal cancer cells.
Human umbilical vein endothelial cells
Matrix metalloproteinase 9
Cyclin dependent kinase
Proliferating cell nuclear antigen
Vascular endothelial growth factor
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
Enzyme-linked immunosorbent assay enzyme-linked immunospecific assay.
This work was supported by National Foundation of Korea (NRF) grant funded by the Korea government [MEST] (No. 2012–0005755).
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