Yanghe decoction (阳和汤) attenuated pain hypersensitivity induced by michigan cancer foundation-7 injection in rats with bone metastases from breast cancer by inhibiting transient receptor potential ankyrin 1

doi:10.19852/j.cnki.jtcm.20220707.001

Journal of Traditional Chinese Medicine ›› 2022, Vol. 42 ›› Issue (6): 948-955.DOI: 10.19852/j.cnki.jtcm.20220707.001

• Research Articles • Previous Articles Next Articles

Yanghe decoction (阳和汤) attenuated pain hypersensitivity induced by michigan cancer foundation-7 injection in rats with bone metastases from breast cancer by inhibiting transient receptor potential ankyrin 1

GONG Hui¹, LI Yang⁴, FENG Lei¹, XIAO Yujie², HUANG Lizhong², MAO Dan³(), ZHANG Hui⁵()

1 Department of Medical Oncology, Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha 410006, China
2 Department of Medical Oncology,Hunan University of Chinese Medicine, Changsha 410208, China
3 Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, Changsha, China
4 Department of Medical Oncology, Hunan Cancer Hospital, Changsha 410031, China
5 Department of Medical Oncology, Hainan Hospital of Traditional Chinese Medicine, Haikou 570203, China

Received:2021-09-26 Accepted:2021-12-21 Online:2022-12-15 Published:2022-07-07
Contact: FENG Lei,XIAO Yujie,HUANG Lizhong,MAO Dan,ZHANG Hui
About author:ZHANG Hui, Department of Medical Oncology, Hainan Hospital of Traditional Chinese Medicine, Haikou 570203, China. zhanghui20202021@163.com, Telephone: +86-731-85295242
MAO Dan, Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha 410011, China. maodan@csu.edu.cn;
Supported by:
Pathogenesis of “Impassability Leads to Pain” about Bone Metastasis based on Proinflammatory Cytokines Activate TRPA1(2018M632971);Study on the Effect and Mechanism of Yanghe Decoction Regulating cxcl12/cxcr4 Biological Axis against Bone Metastasis of Breast Cancer in Yang Deficiency Syndrome(2020JJ8088);Study on the Mechanism of Bone Loss in Breast Cancer Bone Metastasis by Warm Yang Method from the Pathway of TNF-α/NF-κB/Autophagy(2021JJ30418);Clinical Efficiency of Liushen Pill in Treatment of Bone Cancer Pain and Study on the Analgesic Mechanism of Bone Cancer Pain of Rat Model(ZDYF2021SHFZ225)

Abstract

Abstract:

OBJECTIVE: To study the effect and underlying mechanisms of Chinese medicine Yanghe decoction (阳和汤) on pain relief in a rat model of bone metastasis of breast cancer induced by michigan cancer foundation-7 (MCF-7).

METHODS: Bone pain was induced in the tibia of rats injected with MCF-7 cells. The Chinese herbal remedy was used to decoct Yanghe decoction for the treatment of bone pain rats. The behavior study was carried out to evaluate the paw mechanical withdraw threshold and thermal withdraw latency. Liquid chromatography-mass spectrometry, Western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), immunohistochemical (IHC) staining were performed for analysis.

RESULTS: Yanghe decoction could improve the defensive behavior similar to the transient receptor potential ankyrin 1 (TRPA1) inhibitor. In morphology study, Yanghe decoction could attenuate the cellular growth as well as inflammatory infiltration in the metastasis group. Furthermore, Yanghe decoction downregulated the TRPA1 expression on the dorsal root ganglion from the metastatic rats at both transcriptional and protein level. Yanghe decoction alleviated the inflammation in metastatic tissues by hematoxylin-eosin and IHC analysis, and Yanghe decoction also reduced the inflammatory cytokines production in the serum including tumor necrosis factor-α and interleukin-6, interleukin-1 beta by ELISA. As the cytochromec oxidase subunit II/prostaglandin E2 (PGE2) is required for cancer development, Yanghe decoction reduced the expression of PGE2 in the tissue and serum.

CONCLUSION: Taken together, Yanghe decoction protected the rats from breast cancer bone metastasis through TRPA1 signaling mediated neuropathic pain and additional immune modulation in tumor microenvironment.

Key words: bone neoplasms, bone metastasis, Pain, hypersensitivity, TRPA1 cation channel, inflammatory cytokines, Yanghe decoction

GONG Hui, LI Yang, FENG Lei, XIAO Yujie, HUANG Lizhong, MAO Dan, ZHANG Hui. Yanghe decoction (阳和汤) attenuated pain hypersensitivity induced by michigan cancer foundation-7 injection in rats with bone metastases from breast cancer by inhibiting transient receptor potential ankyrin 1[J]. Journal of Traditional Chinese Medicine, 2022, 42(6): 948-955.

Figures/Tables 4

Figure 1 YHD attenuated pain in the metastasis model in behavior study A: the 14-day duration paw mechanical withdraw threshold; B: thermal withdraw latency observation for cold; C: thermal withdraw latency observation for heat. S group: sham operation treat with PBS; Y group: sham operation of rats treated with 18 g • kg-1 • d-1 Yanghe decoction; M group: bone cancer metastasis of rats treated with PBS; M+Y group: rats were injected with MCF-7 before treated with 18 g • kg-1 • d-1 Yanghe decoction; M + T group: rats were injected with MCF-7 transfected with pEGFP-TRPA1; M + T + Y group: rats were injected with MCF-7 transfected with pEGFP-TRPA1 before treated with 18 g • kg-1 • d-1 Yanghe decoction. Measurements were taken from day 0 until day 14. S: sham; Y: YHD; M: metastasis; T: oe-TRPA1; oe: overexpression; YHD: Yanghe decoction; TRPA1: transient receptor potential ankyrin 1; ANOVA: analysis of variance. aP < 0.05, compared with Sham; bP < 0.05, compared with Metastasis; cP < 0.05, compared with Metastasis + oe-TRPA1. P < 0.05 was considered to be statistically significant. The data from each group with five rats were recorded. Data comparison at different time points was analyzed by Bonferroni-corrected repeated measures ANOVA.

Figure 2 YHD mediated morphology changes in tissues of metastasis rat model A: HE staining sections of rat tibia tissue of Sham group; A1: rat tibia tissue of Sham group (×100, Scale bar = 100 µm); A2: rat tibia tissue of Sham group (× 400, Scale bar = 25 µm); B: rat tibia tissue of YHD group; B1: rat tibia tissue of YHD group (× 100, Scale bar = 100 µm); B2: rat tibia tissue of YHD group (× 400, Scale bar = 25 µm); C: Rat tibia tissue of Metastasis group; C1: rat tibia tissue of Metastasis group (×100, Scale bar = 100 µm); C2: rat tibia tissue of Metastasis group (× 400, Scale bar = 25 µm); D: rat tibia tissue of Metastasis + YHD group; D1: rat tibia tissue of Metastasis + YHD group (×100, Scale bar = 100 µm); D2: rat tibia tissue of Metastasis + YHD group (×400, Scale bar = 25 µm); E: rat tibia tissue of Metastasis + oe-TRPA1 group; E1; rat tibia tissue of Metastasis + oe-TRPA1 group (×100, Scale bar = 100 µm); E2: rat tibia tissue of Metastasis + oe-TRPA1 group (×400, Scale bar = 25 µm); F: rat tibia tissue of Metastasis + oe-TRPA1 + YHD group; F1: rat tibia tissue of Metastasis + oe-TRPA1 + YHD group (×100, Scale bar = 100 µm); F2: rat tibia tissue of Metastasis + oe-TRPA1 + YHD group (× 400, Scale bar = 25 µm). Sham: sham operation treat with PBS; YHD : sham operation of rats treated with 18 g•kg-1•d-1 Yanghe decoction; Metastasis: bone cancer metastasis of rats treated with PBS; Metastasis + YHD: rats were injected with MCF-7 before treated with 18 g • kg-1 • d-1 Yanghe decoction; Metastasis + overexpression (oe)-TRPA1: rats were injected with MCF-7 transfected with pEGFP-TRPA1; Metastasis+oe-TRPA1 + YHD: rats were injected with MCF-7 transfected with pEGFP-TRPA1 before treated with 18 g • kg-1 • d-1 Yanghe decoction. Measurement after 14 d of Yanghe decoction intervention. S: Sham; Y: YHD; M: Metastasis; T: oe-TRPA1; HE: hematoxylin-eosin; YHD: Yanghe decoction; PBS: phosphate buffer saline; TRPA1: transient receptor potential ankyrin 1; oe: overexpression; pEGFP: plasmid enhanced green fluorescent protein; MCF-7: michigan cancer foundation-7.

Figure 3 YHD affected the expression of TRPA1 on DRG in vivo A: qRT-PCR was conducted to detect the mRNA expression of TRPA1; B: Western blot was conducted to detect the protein expression of TRPA1; C: the level of TRPA1 protein; D: Western blot was conducted to detect the protein expression of TNF-α and IL-6, IL-1β and PGE2; E: the level of TNF-α, IL-6, IL-1β and PEG2 protein. Sham: sham operation treat with PBS; YHD : sham operation of rats treated with 18 g•kg-1•d-1 Yanghe decoction; Metastasis: bone cancer metastasis of rats treated with PBS; Metastasis + YHD: rats were injected with MCF-7 before treated with 18 g • kg-1 • d-1 Yanghe decoction; Metastasis+overexpression (oe)-TRPA1: rats were injected with MCF-7 transfected with pEGFP-TRPA1; Metastasis + oe-TRPA1 + YHD: rats were injected with MCF-7 transfected with pEGFP-TRPA1 before treated with 18 g • kg-1 • d-1 Yanghe decoction. Measurement after 14 d of Yanghe decoction intervention. S: Sham; Y: YHD; M: metastasis; T: oe-TRPA1; TRPA1: transient receptor potential ankyrin 1; YHD: Yanghe decoction; TNF-α: tumor necrosis factor-α; IL-6: interleukin 6; IL-1β: interleukin 1 beta; PGE2: prostaglandin E2; oe: overexpression; DRG: dorsal root ganglion. qRT-PCR: quantitative real-time polymerase chain reaction. aP < 0.05, compared with Sham; bP < 0.05, compared with Metastasis; cP < 0.05, compared with Metastasis + oe-TRPA1. P < 0.05 was considered to be statistically significant. One-way analysis of variance among multiple groups, followed by Tukey’s post-hoc tests.

Figure 4 YHD decreased the inflammation in the metastasis model A: IHC staining sections of rat tibia tissue were observed under microscope and representative images were taken for the detection of TNF-α, the signature inflammatory cytokine. A1: IHC staining sections of rat tibia tissue of Sham group. A2: IHC staining sections of rat tibia tissue of YHD group. A3: IHC staining sections of rat tibia tissue of Metastasis + YHD group. A4: IHC staining sections of rat tibia tissue of Metastasis + oe-TRPA1 group. A5: IHC staining sections of rat tibia tissue of Sham group. A6: IHC staining sections of rat tibia tissue of Metastasis + oe-TRPA1 + YHD group. The serum levels of PGE2 (B), The level of TNF-α (C), The level of IL-6 (D), The level of IL-1β (E) from groups measured by ELISA. Sham: sham operation treat with PBS; YHD : sham operation of rats treated with 18 g • kg-1 • d-1 Yanghe decoction; Metastasis: bone cancer metastasis of rats treated with PBS; Metastasis + YHD: rats were injected with MCF-7 before treated with 18 g•kg-1•d-1 Yanghe decoction; Metastasis + overexpression (oe)-TRPA1: rats were injected with MCF-7 transfected with pEGFP-TRPA1; Metastasis+oe-TRPA1 + YHD: rats were injected with MCF-7 transfected with pEGFP-TRPA1 before treated with 18 g • kg-1 • d-1 Yanghe decoction. Measurement after 14 d of Yanghe decoction intervention. TRPA1: transient receptor potential ankyrin 1; YHD: Yanghe decoction; TNF-α: tumor necrosis factor-α; IL-6: interleukin 6; IL-1β: interleukin 1 beta; PGE2: prostaglandin E2; oe: overexpression; IHC: immunohistochemistry; ELISA: enzyme-linked immunosorbent assay. aP < 0.05 compared with Sham; bP < 0.05 compared with Metastasis; cP < 0.05 compared with Metastasis + oe-TRPA1. P < 0.05 was considered to be statistically significant. One-way analysis of variance among multiple groups, followed by Tukey’s post-hoc tests.

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Yanghe decoction (阳和汤) attenuated pain hypersensitivity induced by michigan cancer foundation-7 injection in rats with bone metastases from breast cancer by inhibiting transient receptor potential ankyrin 1

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