Bornyl acetate extracted from Sharen (Fructus Amomi) inhibits proliferation, invasion and induces apoptosis by suppressing phosphatidylinositol-3-kinase/protein kinase B signaling in colorectal cancer

doi:10.19852/j.cnki.jtcm.20231018.002

Abstract

Abstract:

OBJECTIVE: To investigate the antitumor effects of bornyl acetate (BA) isolated from Sharen (Fructus Amomi) in colorectal cancer (CRC) and the underlying mechanisms.
METHODS: SW480 and HT29 cells were treated with increasing doses of BA in order to determine its antitumor effects in vitro. Cell viability, colony formation, cell cycle, and apoptosis as well as migration and invasion were assessed using various assays. In addition, the in vivo antitumor effects of BA were assessed using a xenograft mouse model. We then assessed the mechanism of action of BA by conducting pathway activator-mediated rescue experiments and assessed the protein levels by Western blot analysis.
RESULTS: BA showed anti-CRC tumor activities in vitro by suppressing cell proliferation and colony formation, inducing apoptosis, blocking cell cycle, and inhibiting migration and invasion. These effects were mediated via suppression of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway. In the tumor xenograft experiment, BA was found to repress tumor growth in vivo with low toxicity.
CONCLUSIONS: The results demonstrated that BA exerts antitumor effects by suppressing the PI3K/AKT pathway, with low toxicity. Thus, BA might be a potential novel therapeutic agent for CRC.

Key words: bornyl acetate, colorectal neoplasms, phosphatidylinositol 3-kinase, protein kinases B, signal transduction

LI Xiaohua, DUAN Zhihang, YUE Jianjun, ZHANG Yongyu, LI Yihang, LIU Shifang, NIE Qu, YANG Depo, ZHANG Lixia. Bornyl acetate extracted from Sharen (Fructus Amomi) inhibits proliferation, invasion and induces apoptosis by suppressing phosphatidylinositol-3-kinase/protein kinase B signaling in colorectal cancer[J]. Journal of Traditional Chinese Medicine, 2023, 43(6): 1081-1091.

Figures/Tables 4

Figure 1 BA induces apoptosis and blocks cell cycle of CRC A, B: effect of DMSO and increasing concentration of BA on SW480 and HT29 cells cycle arrest. A1: the percentage of SW480 cell at G1/S/G2/M phases of control group; A2: the percentage of SW480 cell at G1/S/G2/M phases of DMSO group; A3: the percentage of SW480 cell at G1/S/G2/M phases of BA low-dose group; A4: the percentage of SW480 cell at G1/S/G2/M phases of BA middle-dose group; A5:the percentage of SW480 cell at G1/S/G2/M phases of BA high-dose group; A6: the percentage of HT29 cell at G1/S/G2/M phases of control group; A7: the percentage of HT29 cell at G1/S/G2/M phases of 0.2% DMSO group; A8: the percentage of HT29 cell at G1/S/G2/M phases of BA low-dose group; A9: the percentage of HT29 cell at G1/S/G2/M phases of BA middle-dose group; A10: the percentage of HT29 cell at G1/S/G2/M phases of BA high-dose group; B1: ratio of G1, S and G2/M period of SW480 cell; B2: ratio of G1, S and G2/M period of HT29 cell (n = 6). C: protein expression image of cleaved-caspase 3 and caspase 9 of SW480 and HT29. 1: protein expression image of cleaved-caspase 3 and caspase 9 of SW480 cell in control group; 2: protein levels of cleaved-caspase 3 and caspase 9 of SW480 cell in DMSO group; 3: protein expression image of cleaved-caspase 3 and caspase 9 of SW480 cell in BA low-dose group; 4: protein expression image of cleaved-caspase 3 and caspase 9 of SW480 cell treated in BA middle-dose; 5: protein expression image of cleaved-caspase 3 and caspase 9 of SW480 cell in BA high-dose group; 6: protein expression image of cleaved-caspase 3 and caspase 9 of HT29 cell in control group; 7: protein levels of cleaved-caspase 3 and caspase 9 of HT29 cell in DMSO group; 8: protein expression image of cleaved-caspase 3 and caspase 9 of HT29 cell in BA low-dose group; 9: protein expression image of cleaved-caspase 3 and caspase 9 of HT29 cell treated in BA middle-dose; 10: protein expression image of cleaved-caspase 3 and caspase 9 of HT29 cell in BA high-dose group. D: relative protein level of cleaved-caspase 3 and caspase 9 of SW480 cell (n = 6). E: relative protein level of cleaved-caspase 3 and caspase 9 of HT29 cell (n = 6). Control group: the cells were cultured in a complete medium containing DMEM, 10% FBS, and 1% penicillin-streptomycin solution; DMSO group: the cells were treated with 0.2% DMSO; BA low-dose group: the cells were given 1.975 μg/mL BA; BA middle-dose group: the cells were given 3.95 μg/mL BA; BA high-dose group: the cells were given 7.8125 μg/mL BA. BA: bornyl acetate; CRC: colorectal cancer; DMSO: dimethyl sulfoxide; DMEM: dulbecco's modified eagle medium; FBS: fetal bovine serum; G1: gap1, the gap time from the completion of mitosis to the start of DNA replication; S: synthesis phase, the period of DNA replication; G2/M: gap2/mitosis, the ratio of the period from the completion of DNA replication to the beginning of mitosis and mitosis. Data are presented as mean ± standard error of mean. aP < 0.05, bP < 0.01, and cP < 0.001, compared with control group.

Figure 2 BA inhibits migration and invasion of CRCs A: SW480 and HT29 cells migration ability after treated with increasing concentration of BA at 0 and 24 h, × 40. A1: the migration ability of SW480 cell at 0 h in control group; A2: the migration ability of SW480 cell at 0 h in DMSO group; A3: the migration ability of SW480 cell at 0 h in BA low-dose group; A4: the migration ability of SW480 cell at 0 h in BA middle-dose group; A5: the migration ability of SW480 cell at 0 h in BA high-dose group; A6: the migration ability of SW480 cell at 24h in control group; A7: the migration ability of SW480 cell at 24 h in DMSO group; A8: the migration ability of SW480 cell at 24 h in BA low-dose group; A9: the migration ability of SW480 cell at 24 h in BA middle-dose group; A10: the migration ability of SW480 cell at 24 h in BA high-dose group; A11: the migration ability of HT29 cell at 0 h in control group; A12: the migration ability of HT29 cell at 0 h in DMSO group; A13: the migration ability of HT29 cell at 0 h in BA low-dose group; A14: the migration ability of HT29 cell at 0 h in BA middle-dose group; A15: the migration ability of HT29 cell at 0 h in BA high-dose group; A16: the migration ability of HT29 cell at 24h in control group; A17: the migration ability of HT29 cell at 24 h in DMSO group; A18: the migration ability of HT29 cell at 24 h in BA low-dose group; A19: the migration ability of HT29 cell at 24 h in BA middle-dose group; A20: the migration ability of HT29 cell at 24 h in BA high-dose group. B: the migration cells percentage of SW480 and HT29 (n = 6). C: the invasion ability cells of SW480 and HT29 cells treated with increasing concentrations of BA, ×40. C1: the invasion ability of SW480 cell at 24 h of control group; C2: the invasion ability of SW480 cell at 24 h of DMSO group; C3: the invasion ability of SW480 cell at 24 h of BA low-dose group; C4: the invasion ability of SW480 cell at 24 h of BA middle-dose group; C5: the invasion ability of SW480 cell at 24 h of BA high-dose group; C6: the invasion ability of HT29 cell at 24h of control group; C7: the invasion ability of HT29 cell at 24 h of DMSO group; C8: the invasion ability of HT29 cell at 24 h of BA low-dose group; C9: the invasion ability of HT29 cell at 24 h of BA middle-dose group; C10: the invasion ability of HT29 cell at 24 h of BA high-dose group. D: the invaded cell percentage of SW480 and HT29 (n = 6). Control group: the cells were cultured in a complete medium containing DMEM, 10% FBS, and 1% penicillin-streptomycin solution; DMSO group: the cells were treated with 0.2% DMSO; BA low-dose group: the cells were given 1.975 μg/mL BA; BA middle-dose group: the cells were given 3.95 μg/mL BA; the high-dose group: the cells were given 7.8125 μg/mL BA. BA: bornyl acetate; CRCs: colorectal cancers; DMSO: dimethyl sulfoxide; DMEM: dulbecco's modified eagle medium; FBS: fetal bovine serum. Data are presented as mean ± standard error of mean. aP < 0.05, bP < 0.001, and eP < 0.01, compared with control group; cP < 0.05 and dP < 0.001, compared with low-dose group; gP < 0.001 and fP < 0.01, compared with middle-dose group.

Figure 3 BA inhibits SW480 cell migration and invasion via inhibiting PI3K/AKT pathway A: the migration ability of SW480 cell treated with different administration, × 40. A1: the migration ability at 0 h in control group; A2: the migration ability at 0 h in 0.2% DMSO group; A3: the migration ability at 0 h in 7.8125 μg/mL BA group; A4: the migration ability at 0 h in 7.8125 μg/mL BA+LY294002 group; A5: the migration ability at 0 h in 7.8125 μg/mL BA + 740Y-P group; A6: the migration ability at 24 h in control group; A7: the migration ability at 24 h in DMSO group; A8: the migration ability at 24 h in 7.8125 μg/mL BA group; A9: the migration ability at 24 h in 7.8125 μg/mL BA + LY294002 group; A10: the migration ability at 24 h in 7.8125 μg/mL BA + 740Y-P group. B: the migration cells percentage of SW480 (n = 6). C: The invasion ability of SW480 cells treated with different administration at 24 h. ×40. C1: the invasion ability of control group; C2: the invasion ability of DMSO group; C3: the invasion ability of 7.8125 μg/mL BA group; C4: the invasion ability of 7.8125 μg/mL BA + LY294002 group; C5: the invasion ability of 7.8125 μg/mL BA + 740Y-P group. D: the invaded cells percentage of SW480 (n = 6). E: the P85, phosphorylation of P85, AKT and phosphorylation of AKT protein levels of SW480 cells treated with different administration by WB method. ×40. 1: control group; 2: DMSO group; 3: 7.8125 μg/mL BA group; 4: 7.8125 μg/mL BA + LY294002 group; 5: 7.8125 μg/mL BA + 740Y-P group. F: the relative protein levels of SW480cells (n = 6). Control group: the cells were cultured in a complete medium containing DMEM, 10% FBS, and 1% penicillin-streptomycin solution; DMSO group: the cells were treated with 0.2% DMSO. BA: bornyl acetate; PI3K/AKT: phosphatidylinositol-3-kinase/protein kinase B; DMSO: dimethyl sulfoxide; DMEM: dulbecco's modified eagle medium; FBS: fetal bovine serum; WB: Western blotting; 740Y-P: 740YPDGFR; LY294002: 2-morpholino-8-phenyl-4-oxo-4H-1-benzopyran. Data are presented as mean ± standard error of mean. aP < 0.001, compared with control group; bP < 0.001, cP < 0.05, and dP < 0.01, compared with 7.8125 μg/mL BA group; eP < 0.001, compared with 7.8125 μg/mL BA + 740Y-P group.

Figure 4 BA represses tumor growth in vivo SW480 cells were pretreated with TGF-β prior to their transplantation into mice, and then intraperitoneally injected with 0.2 mL BA (5 mg/kg, 2 mg/kg) or intraperitoneally co-injected with 0.2 mL BA (5, 2 mg/kg) and 2 mg/mL 740 Y-P. A-C: The tumors volume, tumor size and body weight of mice in different groups, × 10. A1: control group; A2: TGF-β group; A3: low-dose BA group; A4: high-dose BA group; A5: low-dose BA + PI3K group; A6: high-dose BA + PI3K group. D-F: the pathology of tumors was analyzed by HE and IHC staining, × 40. D1: hepatic histological of control group; D2: hepatic histological of 10 ng/mL TGF-β group; D3: hepatic histological of low-dose BA group; D4: hepatic histological of High-dose BA group; D5: hepatic histological of low-dose BA + PI3K group; D6: hepatic histological of high-dose BA + PI3K group. E1: E-cadherin protein expression level of control group; E2: E-cadherin protein expression level of TGF-β group; E3: E-cadherin protein expression level of high-dose BA group; E4: E-cadherin protein expression level of high-dose BA + PI3K group; E5: N-cadherin protein expression level of control group; E6: N-cadherin protein expression level of TGF-β group; E7: N-cadherin protein expression level of high-dose BA group; E8: N-cadherin protein expression level of high-dose BA + PI3K group. G, H: the protein levels of P85, AKT as well as phosphorylation of P85 and AKT analyzed by WB. 1: control group; 2:10 ng/mL TGF-β group; 3: high-dose BA group; 4: high-dose BA + PI3K group (n = 3). Control group: mice were injected with 200 μL SW480 cells at a density of 5.0×106 cells/mL until tumor growth to 100 mm3, and then administered intraperitoneal injection of 0.2 mL saline each day for 14 d. The remaining mice were injected with 200 μL SW480 cells pretreated with 10 ng/mL TGF-β until the tumors grew to 100 mm3. TGF-β group: mice were administered intraperitoneal injection of 0.2 mL saline per day for 14 d; low-dose BA group: mice received intraperitoneal injection of 0.1 mL BA (2 mg/kg) for 14 d; high-dose BA group: mice received intraperitoneal injection of 0.2 mL BA (5 mg/kg) for 14 d; low-dose BA + PI3K group: mice received intraperitoneal injection of 0.1 mL BA (2 mg/kg) and 0.1 mL 740 Y-P (10 mg/kg) for 14 d; high-dose BA + PI3K group: mice received intraperitoneal injection of 0.2 mL BA (5 mg/kg) and 0.1 mL 740 Y-P (10 mg/kg) for 14 d. BA: bornyl acetate; TGF-β: transforming growth factor beta; 740 Y-P: 740YPDGFR; PI3K: phosphatidylinositol-3-kinase; P85: PI3 kinase p85 antibody; AKT: protein kinase B; WB: western blotting; HE: hematoxylin and eosin; IHC: immunochemistry. Data are presented as mean ± standard error of mean. aP < 0.05, bP < 0.01 and cP < 0.001, compared with TGF-β group; dP < 0.05, compared with high-dose BA group; eP < 0.05, compared with control group; fP < 0.001 and gP < 0.001, compared with high-dose BA + PI3K group.

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