Caffeic acid 3,4-dihydroxyphenethyl ester prevents colorectal cancer through inhibition of multiple cancer-promoting signal pathways in 1,2-Dimethylhydrazine/dextran sodium sulphate mouse model

doi:10.19852/j.cnki.jtcm.20231204.001

Abstract

Abstract:

OBJECTIVE: To elucidate the potential feature and mechanism of the caffeic acid 3,4-dihydroxyphenethyl ester (CADPE) molecule, which can prevent colorectal cancer (CRC) in the 1,2-Dimethylhydrazine (DMH)/dextran sodium sulphate (DSS)-induced mouse model.

METHODS: Institute of cancer research (ICR) male mice were injected with 20 mg/kg DMH for a week. After that, 2% DSS was administered in the drinking water for another 7 d. The CADPE treatment was given to the DMH/DSS induced male mice at three different periods until their sacrifice. Histopathological examination was used for observing the CRC development at colonic mucosa. Immunohistochemistry (IHC), blood cells smearing and crypt damage scoring methods were used for investigating the anti-inflammation feature of CADPE related to CRC. The reversing targets searching method was applied with artificial intelligence (AI), computer-aided drug designing (CADD) and Ingenuity Pathway Analysis (IPA) techniques for predicting the potential targets and mechanism of CADPE highly related to CRC.

RESULTS: The data indicated that CADPE inhibited CRC tumor development in the colitis-associated DMH/DSS induced mouse model after giving the early treatment. CADPE also impeded the acute inflammation by decreasing the infiltration of neutrophils significantly during the initial stage of CRC development. Finally, our data showed that CADPE prevented CRC by blocking active sites of three pivotal protein targets including epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) in two major cancer development pathways.

CONCLUSIONS: CADPE effectively prevented CRC at early stage of tumor germination in the DMH/DSS mouse model highly likely due to its anti-acute inflammation characteristic and the ability of blocking EGFR, ERK and mTOR activities in two highly related CRC developing pathways.

Key words: caffeic acids, colorectal neoplasms, inflammation, chemoprevention, Sarcandra glabra

JIN Tao, ZHOU Qian, SHEN Jichen, ZHANG Zhizhong, LIAN Xiaoyuan. Caffeic acid 3,4-dihydroxyphenethyl ester prevents colorectal cancer through inhibition of multiple cancer-promoting signal pathways in 1,2-Dimethylhydrazine/dextran sodium sulphate mouse model[J]. Journal of Traditional Chinese Medicine, 2024, 44(1): 70-77.

Figures/Tables 4

Figure 1 CADPE reduced production of inflammation and inhibited NF-κB activation in DMH/DSS induced CRC in vivo A: different images showed the CADPE treatment DMH/DSS induced male mice had fewer tumors in the colon than the model group male mice and without the effect of toxicity was found. A1, A2: na?ve group, only treated with water; A3, A4: model group, treated with DMH/DSS; A5, A6: 5-FU group, treated with 5-FU; A7, A8: CADPE group, treated with 15 mg/kg CADPE; A9, A10: CADPE group, treated with 25 mg/kg CADPE; A11, A12: CADPE group, treated with 35 mg/kg CADPE. B: HE staining images of three mouse groups na?ve (B1-B3), model (B4-B6) and CADPE (B7-B9). demonstrated the core incidence area of CRC in colons under ×4, ×40 and ×100 magnification. C: HE staining images of na?ve (C1-C3), model (C4-C6) and CADPE (C7-C9) at three time points (days 15, 18 and 25) showed the inflammation and crypt damage in colonic mucosa under ×40 magnification. CADPE: Caffeic acid 3,4-dihydroxyphenethyl ester; DMH/DSS: 1,2-Dimethylhydrazine/dextran sodium sulphate; HE: hematoxylin and eosin.

Figure 2 CADPE prevented the inflammation and colorectal cancer progression by inhibiting the infiltration of immune cells from the peripheral blood. A: three samples from Model mouse group (A1-A3): treated only with DMH (20 mg/kg) and DSS (2%) for two weeks; three samples from CADPE treatment mouse group (A4-A6): treated with DMH/DSS for two weeks and CADPE (25 mg/kg) for twelve weeks. The immunohistochemistry images of mouse groups model (A1-A3) and CADPE (A4-A6) marked by CD3 under × 40 magnification domostrated that tumor tissues were surrounding by more brown colored positive cells from the peripheral blood in the model mouse group samples than the CADPE treatment group samples. B: image of the polymorphic immune cells from the mouse peripheral blood was observed under microscope at ×100 magnification. C: expression level of neutrophils and its tendency between the CADPE treatment (25 mg/kg) and model mouse groups were compared at the 15th, 18th and 25th day. D: expression level of lymphocytes and its tendency between the CADPE treatment (25 mg/kg) and model mouse groups were compared at the 15th, 18th and 25th day. Data are presented as mean ± standard deviation; n = 7 for each group; one-way analysis of variance followed by Dunnett's multiple comparison (C, D); aP < 0.05 compared with the model group. CADPE: Caffeic acid 3, 4-dihydroxyphenethyl ester; DMH: the 1, 2-Dimethylhydrazine; DSS: dextran sodium sulphate.

Figure 3 CADPE reduced tumor growth of CRC via blocking three potential targets and two cancer related pathways A: the molecular simulation data indicated that the small CADPE molecule was tighly binding the surface of the epidermal growth factor receptor (EGFR) active site; B: the molecular simulation data showed that the small CADPE molecule was tighly binding the surface of the mTOR active site; C: the molecular simulation data demonstrated that the small CADPE molecule was tighly binding the surface of the ERK active site. The arrows indicated the amplified locations. CADPE: Caffeic acid 3,4-dihydroxyphenethyl ester; EGFR: epidermal growth factor receptor; CRC: colorectal cancer; mTOR: the mechanistic target of rapamycin.

Figure 4 Summary chart of CADPE mechanism in the MAPK/ERK and PI3K-AKT-mTOR pathways EGFR: epidermal growth factor receptor; RAS: ras protein kinase; RAF: Raf protein kinase; CADPE: Caffeic acid 3,4-dihydroxyphenethyl ester; MAPK/ERK: mitogen-activated protein kinases/extracellular signal-regulated kinase; NF-κB: nuclear factor-kappa B; PI3K-AKT-mTOR: phosphatidylinositol three kinase AK strain transforming-mammalian target of rapamycin.

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