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Free PDF Download European Review for Medical and Pharmacological Sciences 2021; 25: 2331-2343 Anlotinib inhibits the progress of colorectal cancer cells by antagonizing VEGFR/JAK2/STAT3 axis Z.-X. JIA1,2, Z. ZHANG3, Z. LI1,2, A. LI1,2, Y.-N. XIE1,2, H.-J. WU1,2, Z.-B. YANG4, H.-M. ZHANG1,2, X.-M. ZHANG1,2 1School of Public Health, North China University of Science and Technology, Tangshan, China 2College of Life Science, North China University of Science and Technology, Tangshan, China 3Affliated Tangshan Gongren Hospital, North China University of Science and Technology, Tangshan, China 4School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, China Zhenxian Jia and Zhi Zhang contributed equally to this work Abstract. – OBJECTIVE: Anlotinib, a nov- CONCLUSIONS: These findings suggested el tyrosine kinase receptor inhibitor (TKI), tar- that anlotinib might benefit colorectal cancer gets multi-targets, including vascular endothe- therapy by antagonizing VEGFR/JAK2/STAT3 lial growth factor receptor (VEGFR). Increasing signaling. Our study may provide new insights evidence suggests that anlotinib exhibits effec- into novel molecular therapeutic strategies for tive anti-tumor activity in various cancer types, colorectal cancer. such as liver cancer. However, the biological function of anlotinib in the treatment of colorec- Key Words: tal cancer (CRC) remains largely unknown. This Anlotinib, Cisplatin, VEGFR, STAT3, Colorectal can- investigation aims to investigate the function cer. and possible molecular mechanism of anlotinib in CRC therapy. MATERIALS AND METHODS: Human col- orectal cancer cells (HCT-116 and LOVO) were Introduction cultured and treated with anlotinib alone or com- bined with cisplatin (DDP). Thereafter, CCK8 as- say, CyQUANT NF assay, and colony formation Colorectal cancer (CRC) has been proved as were used to determine the cytotoxicity prop- the third most commonplace reason for the deaths erty and cell proliferation of colorectal cancer. caused by cancer around the world. Also, it is To evaluate the invasion and metastasis of col- predicted that CRC will be of higher and higher orectal cancer cells, we conducted wound heal- incidence over time1. As for the deaths due to ing and trans-well assay. Hoechst33342 fluo- CRC, metastasis is the most important reason2,3. rescence staining and Flow Cytometry analysis At present, the standard treatment of CRC is were applied for apoptosis detection. Real-time adjuvant chemotherapy after surgery, which usu- qPCR and Western blot were used to measure 4 the mRNA or protein level. ally involves in platinum-based drugs . In spite RESULTS: Our results showed anlotinib alone of the fact that the Cisplatin (DDP) has been or combined with cisplatin inhibited cell pro- recognized as a first-rate chemotherapeutic drug liferation, migration, and invasion and activat- for the treatment of solid tumors, which assumes ed apoptosis in colorectal cancer cells. Fur- an irreplaceable role of DDP in the therapy for thermore, we found that anlotinib inhibiting the CRC5,6, the treatment is still accompanied by phosphorylation level of VEGFR, Janus Kinase drug resistance and reduced effectiveness7-9. It is 2 (JAK2), and Signal Transducer and Activator of Transcription 3 (STAT3). Combination chemo- a pressing need to develop a more effective tar- therapy of anlotinib with cisplatin is more sensi- geted drug for CRC treatment alone or combined tive to colorectal cancer. with chemotherapy. Corresponding Author: Xuemei Zhang, MD; e-mail: [email protected] 2331 Z.-X. Jia, Z. Zhang, Z. Li, A. Li, Y.-N. Xie, H.-J. Wu, Z.-B. Yang, H.-M. Zhang, X.-M. Zhang The literature indicated that cisplatin, a che- dissolved in Dimethyl Sulfoxide (DMSO) (Sig- motherapeutic agent for colorectal cancer, cispla- ma-Aldrich, St. Louis, MO, USA) and stored in tin can be more effective through a combination dark at -20°C. Cancer cells were treated with a approach10. Anlotinib (AL3818), as a third-line serial of concentration (0, 2, 4, 8, and 16 μM) broad-spectrum anticancer drug, has been tes- of anlotinib or DDP (0, 2, 4, 8, and 16 μM). For tified to be capable of improving the prognosis the combination treatment, 3 μM anlotinib and of those patients who suffer the advanced Non- 8 μM DDP were applied. Small-Cell Lung Cancer (NSCLC)11-14. For the medullary thyroid carcinoma, which is either Cell Viability and Cell Proliferation Assay locally advanced or metastatic, osteosarcoma, Cytotoxicity property and cell proliferation as well as liver cancer, anlotinib also showed of anlotinib and/or DDP against HCT-116 and effective anti-tumor activity15-17. As a Tyrosine LOVO cells were determined by CCK-8 (Cell Kinase Inhibitor (TKI), the anlotinib targeted Counting Kit-8) assay (Dojindo, Molecular Tech- on several genes, including Fibroblast Growth nologies, Kumamoto, Japan) and CyQUANT NF Factor Receptor (FGFR) and Vascular Endothe- assay (Thermo Fisher Scientific, Waltham, MA, lial Growth Factor Receptor (VEGFR). Many USA), respectively. Briefly, 5×103 colorectal can- researches demonstrated that the increased ex- cer cells for each well were seeded in a 96-well pression of Vascular Endothelial Growth Factor plate and treated with different concentrations of A (VEGFA) is related to the development of anlotinib and/or DDP after 24, 48, or 72 hours. tumor and the prognosis of CRC18-20. VEGFR2, For cytotoxicity detection, after incubated with as a receptor for VEGFA, activates a number of CCK-8 agents for 2 hours, absorbance at 450 nm downstream pathways, such as JAK2/STAT3 sig- was detected. The median lethal dose (LD50) naling, which affects cell proliferation, migration, was calculated using SPSS 23.0 (IBM, Armonk, and tubular formation. Some studies21,22 showed NY, USA). For cell proliferation analysis, cells that several VEGFR2 inhibitors inhibited tumor were labeled with CyQUANT NF reagent. After angiogenesis. incubated with dye binding solution for 10 min, We hypothesized anlotinib alone or combined the fluorescence intensity was measured by a flu- with platinum could improve the treatment of orescence microplate reader. The median inhibi- CRC. We found that anlotinib could inhibit cell tory concentration (IC50) was then calculated by proliferation, invasion and migration, and pro- SPSS 23.0 (IBM, Armonk, NY, USA). mote apoptosis through VEGFR/JAK2/STAT3 signaling pathway. This investigation may pro- Colony-Forming Assay vide a new thought for the clinical treatment of HCT-116 and LOVO cells were seeded in a six- CRC. well plate at 3×105 cells/ml and incubated to 80% confluency. After treated with anlotinib and/or DDP for 24 hours, viable cells were harvested and Material and Methods then incubated in a 60 mm culture dish at 2×103 cells/3 ml for 12 days. Cells were stained with Cell Culture and Treatments crystal violet and observed by an IX71 inverted Human colorectal cancer cells (HCT-116 and microscope (Olympus, Tokyo, Japan). LOVO) were obtained from American Type Culture Collection (ATCC) (Manassas, VA, Cell Migration and Invasion Assays USA). All cells were cultured in Dulbecco’s Transwell chambers (Corning, Corning, NY, Modified Eagle’s Medium (DMEM; Thermo USA) coated with or without Matrigel were ap- Fisher Scientific, Waltham, MA, USA) sup- plied to analyze cell invasion and migration, plied with 100 μg/ml streptomycin, 100 U/ml respectively. Briefly, cells (1×105 cells/well) were penicillin (Solarbio, Beijing, China), and 10% treated with anlotinib and/or DDP for 24 hours Fetal Bovine Serum (FBS; Thermo Fisher Sci- and then were incubated in the upper chamber entific, Waltham, MA, USA) at 37°C with 5% with 200 μL of serum-free DMEM for 24 hours. CO2. Anlotinib was a gift from Chia Tai Tian- The lower chamber filled with the complete me- qing Pharmaceutical company (Nanjing, Ji- dium was fixed with Paraformaldehyde and then angsu, China). Cisplatin (DDP) was purchased dyed with crystal violet. The invasive or migrated from Jiangsu Haosen Pharmaceutical Co., Ltd cells were then counted under an IX71 inverted (Lianyungang, Jiangsu, China). Anlotinib was microscope (Olympus, Tokyo, Japan). 2332 Anlotinib inhibits the progress of colorectal cancer cells by antagonizing VEGFR/JAK2/STAT3 axis Wound healing assays are used to determine Western Blot Analysis collective cell migration. After reached 90% con- Cell lysates were run on 10% or 12% SDS poly- fluence, cells were scraped and then were treated acrylamide gel to separate proteins, which then with anlotinib and/or DDP. The distance between be transferred to Nitrocellulose (NC) membrane. the edges of the wound was measured under After incubated with the specified primary anti- an IX71 inverted microscope (Olympus, Tokyo, body, and then corresponding horseradish perox- Japan). idase (HRP) conjugated secondary antibody, NC membrane was developed by enhanced chemilu- RNA Extraction, cDNA Synthesis, minescence (ECL) luminescence reagents (GE and qPCR Healthcare, Amersham, Buckinghamshire, UK). RNA extraction reagent and RevertAid First β-actin was applied as reference control. All an- Strand cDNA Synthesis Kit were purchased from tibodies were purchased from Abcam (Eugene, Thermo Fisher Scientific company (Waltham, OR, USA). MA, USA). The relative mRNA expression was evaluated by quantitative PCR in ABIPRISM® 7900HT Fast Real-Time PCR System (Thermo Statistical Analysis Fisher Scientific, Waltham, MA, USA). For each Data were analyzed using GraphPad Prism gene, 2-∆∆CT was calculated to determine the rela- 7.0 software (GraphPad Software, La Jolla, CA, tive expression. The primers were listed in Sup- USA) and SPSS 23.0 program (IBM, Armonk, plementary Table I. NY, USA). One-way ANOVA or Student’s t-test method were applied to analyze the differences Analysis of Apoptosis among groups. All tests were two-sided tests. To investigate the apoptosis of colorectal can- p-value less than 0.05 was designed as statistical cer cells after treatment of anlotinib, we used significance. Annexin V-PE (BD Biosciences, San Jose, CA, USA) to label apoptosis cells. Collected colorec- tal cancer cells were resuspended and labeled with 5 μl Annexin V-PE and 5 μl 7-AAD.
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