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Anticancer activity of herbal formula Jisilhaebaekgyeji-Tang against human breast cancer cells and its mechanism

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Abstract

Background

Jisilhaebaekgyeji-Tang (JHG, Zhishi Xiebai Guizhi Tang) is a famous traditional herbal medicine described in the Geumgweyoryak (Jin Gui Yao Lue), an ancient Chinese medical text. JHG is composed of five medicinal herbs and is used to treat thoracic obstructions in China, Japan, and Korea. Although it has been reported the inhibitory effect of JHG against skin and lung cancers, there is a lack of reliable scientific evidence supporting its efficacy.

Objective

In the present study, we investigated the effects of JHG on human breast cancer cell lines and explored the underlying mechanisms. The anticancer effects of the JHG were evaluated in human breast cancer cell lines and human umbilical vein endothelial cells (HUVECs).

Results

An ethanol extract of JHG suppressed the growth of cells representing four subtypes of human breast cancer. In particular, JHG showed the greatest inhibitory effect against MCF-7 cells and was found to significantly reduce the mitochondrial membrane potential. Furthermore, the extract dose-dependently inhibited the expression of BCL-2, MCL-1, survivin, and procaspases-9 and -7 and induced nuclear condensation and fragmentation. In MCF-7 cells, the JHG extract inhibited the phosphorylation of the estrogen receptor alpha (ERα) and the activation of the mTOR and ERK pathways but enhanced the phosphorylation of p38 mitogen-activated protein kinase. In addition, the extract attenuated the hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway under hypoxia-mimicking conditions and inhibited the metastatic ability of MCF-7 cells, including their migration and invasion activities, and the angiogenic properties of HUVECs.

Conclusion

The results suggest that the JHG extract exerts potent anticancer effects and that these effects may be due to the inhibition of ERα and the induction of intrinsic pathway-mediated apoptosis in MCF-7 cells.

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Abbreviations

ANOVA:

Analysis of variance

CAM:

Complementary and alternative medicine

DAPI:

4,6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s modified eagle’s medium

DMSO:

Dimethyl sulfoxide

EGF:

Epidermal growth factor

ELISA:

Enzyme-linked immunosorbent assay

ERα:

Estrogen receptor alpha

FBS:

Fetal bovine serum

HIF-1α:

Hypoxia-inducible factor-1α

HUVECs:

Human umbilical vein endothelial cells

JHG:

Jisilhaebaekgyeji-Tang

MAPK:

Mitogen-activated protein kinases

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide

PBS:

Phosphate-buffered saline

PBST:

PBS containing tween 20

RPMI:

Roswell Park Memorial Institute media

SD:

Standard deviations

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HF21C0129).

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Authors and Affiliations

  1. College of Korean Medicine, Dongguk University, Goyang, 10326, Republic of Korea

    Sang Kyu Jeon, Su Mi Park, Jung Yun Ahn, Ok Hyeon Kim, Young Woo Kim, Sun-Dong Park & Ju-Hee Lee

  2. Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea

    Ok Hyeon Kim

  3. College of Veterinary Medicine, Gyeongsang National University, Jinju, 52828, Republic of Korea

    Kwang-Il Park

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  1. Sang Kyu Jeon
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Contributions

SDP and JHL were responsible for the study design, funding, and supervision. JHL and SKJ participated in the experiments and wrote the manuscript. SMP, JYA, OHK, YWK, and KIP performed the experiments and statistical analysis. All the authors participated in manuscript preparation and approved the final version of the manuscript.

Corresponding authors

Correspondence to Sun-Dong Park or Ju-Hee Lee.

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Conflict of interest

Sang Kyu Jeon declares that he has no conflict of interest. Su Mi Park declares that she has no conflict of interest. Jung Yun Ahn declares that she has no conflict of interest. Ok Hyeon Kim declares that she has no conflict of interest. Young Woo Kim declares that he has no conflict of interest. Kwang-Il Park declares that he has no conflict of interest. Sun-Dong Park declares that he has no conflict of interest. Ju-Hee Lee declares that she has no conflict of interest.

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Jeon, S.K., Park, S.M., Ahn, J.Y. et al. Anticancer activity of herbal formula Jisilhaebaekgyeji-Tang against human breast cancer cells and its mechanism. Mol. Cell. Toxicol. 19, 437–451 (2023). https://doi.org/10.1007/s13273-022-00271-9

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