Total saponins from Rhizoma Panacis Majoris inhibit proliferation, induce cell cycle arrest and apoptosis and influence MAPK signalling pathways on the colorectal cancer cell

Chang,Lu; Zhou,Rui; He,Yihan; Meng,Mei; Hu,Jinhang; Liu,Yanru; Pan,Yalei; Tang,Zhishu; Yue,Zhenggang

doi:10.3892/mmr.2021.12181

Total saponins from Rhizoma Panacis Majoris inhibit proliferation, induce cell cycle arrest and apoptosis and influence MAPK signalling pathways on the colorectal cancer cell

Authors:
- Lu Chang
- Rui Zhou
- Yihan He
- Mei Meng
- Jinhang Hu
- Yanru Liu
- Yalei Pan
- Zhishu Tang
- Zhenggang Yue
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Affiliations: State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation)/Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry/Shaanxi Innovative Drug Research Center, School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P.R. China
Published online on: May 29, 2021 https://doi.org/10.3892/mmr.2021.12181
Article Number: 542
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) ranks third in incidence and second in mortality among all types of cancer, and due to its insidious onset and lack of early symptoms, it is usually diagnosed at a later stage. Saponins, a class of compounds abundant in plants, have been reported to possess prominent anti‑tumour properties. The use of ginsenoside Rg3 in the clinical setting was authorized by the National Medicinal Products Administration of China. In the present study, total saponins from Rhizoma Panacis Majoris (RPMTG) were prepared, and the pharmacological mechanisms underlying the anti‑CRC effects of RPMTG were investigated. The effect of RPMTG on the proliferation, cell cycle progression and apoptosis of HCT116 and SW620 cells were detected by MTT, flow cytometry and western blotting assays, and it was demonstrated that RPMTG could inhibit the proliferation of HCT116 and SW620 cells with IC50 values of 315.8 and 355.1 µg/ml, respectively, induce cell cycle arrest in the S and G0/G1 phase, and trigger apoptosis by downregulating the expression of the anti‑apoptotic proteins Bcl‑2, Bcl‑xL and induced myeloid leukaemia cell differentiation protein Mcl‑1, and increasing the expression of the pro‑apoptotic proteins Bax and Bad, cleaved caspased‑3 and poly(ADP)‑ribose polymerase. These findings suggested that RPMTG induced apoptosis through mitochondrial‑related pathways. In addition, RPMTG also decreased the expression of phosphorylated (p)‑extracellular signal‑regulated kinase and increased p‑c‑Jun N‑terminal kinase (p‑JNK) and p‑p38. Moreover, the effects of RPMTG on cell proliferation and apoptosis were partially reversed when the JNK and p38 mitogen‑activated protein kinase (MAPK) pathways were inhibited, indicating that RPMTG triggered apoptosis mainly via regulating JNK and p38 MAPK signalling. Therefore, RPMTG may have potential as an anti‑CRC agent, and further evaluations are needed.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI
3	Ma M, Wang X, Liu N, Shan F and Feng Y: Low-dose naltrexone inhibits colorectal cancer progression and promotes apoptosis by increasing M1-type macrophages and activating the Bax/Bcl-2/caspase-3/PARP pathway. Int Immunopharmacol. 83:1063882020. View Article : Google Scholar : PubMed/NCBI
4	Sun J, Feng Y, Wang Y, Ji Q, Cai G, Shi L, Wang Y, Huang Y, Zhang J and Li Q: α-hederin induces autophagic cell death in colorectal cancer cells through reactive oxygen species dependent AMPK/mTOR signaling pathway activation. Int J Oncol. 54:1601–1612. 2019.PubMed/NCBI
5	Liu Z, Xiong L, Ouyang G, Ma L, Sahi S, Wang K, Lin L, Huang H, Miao X, Chen W, et al: Investigation of copper cysteamine nanoparticles as a new type of radiosensitiers for colorectal carcinoma Treatment. Sci Rep. 7:92902017. View Article : Google Scholar : PubMed/NCBI
6	Hu M, Yu Z, Mei P, Li J, Luo D, Zhang H, Zhou M, Liang F and Chen R: Correction for: Lycorine induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging (Albany NY). 12:6488–6489. 2020. View Article : Google Scholar : PubMed/NCBI
7	Weaver BA: How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 25:2677–2681. 2014. View Article : Google Scholar : PubMed/NCBI
8	GLB: L. Gatti, ; Perego P and Zaffaroni N: Camptothecin resistance in cancer: Insights into the molecular mecha-nisms of a DNA-damaging drug. Curr Med Chem. 20:1541–1565. 2013. View Article : Google Scholar : PubMed/NCBI
9	Paidakula S, Nerella S, Vadde R, Kamal A and Kankala S: Design and synthesis of 4β-acetamidobenzofuranone-podophyllotoxin hybrids and their anti-cancer evaluation. Bioorg Med Chem Lett. 29:2153–2156. 2019. View Article : Google Scholar : PubMed/NCBI
10	Man S, Gao W, Zhang Y, Huang L and Liu C: Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia. 81:703–714. 2010. View Article : Google Scholar : PubMed/NCBI
11	Choi JS, Chun KS, Kundu J and Kundu JK: Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review). Int J Mol Med. 32:1227–1238. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lee DG, Jang SI, Kim YR, Yang KE, Yoon SJ, Lee ZW, An HJ, Jang IS, Choi JS and Yoo HS: Anti-proliferative effects of ginsenosides extracted from mountain ginseng on lung cancer. Chin J Integr Med. 22:344–352. 2016. View Article : Google Scholar : PubMed/NCBI
13	Sun M, Ye Y, Xiao L, Duan X, Zhang Y and Zhang H: Anticancer effects of ginsenoside Rg3 (Review). Int J Mol Med. 39:507–518. 2017. View Article : Google Scholar : PubMed/NCBI
14	Song X, Wang W, Zhang X, Jiang Y, Yang X, Deng C, Yue Z and Tang Z: Deglucose chikusetsusaponin IVa isolated from Rhizoma Panacis Majoris induces apoptosis in human HepG2 hepatoma cells. Mol Med Rep. 12:5494–5500. 2015. View Article : Google Scholar : PubMed/NCBI
15	Chen T, Chen LF, Jin GQ and Li D: Panax japlcus var induced apoptosis of human hepatocarcinoma cells in vitro. Tumor. 26:144–147. 2006.(In Chinese). PubMed/NCBI
16	Chen T, Chen M, Hu Y, Gong Z and Deng L: Extraction and anticancer activity of polysaccharide from Rhizoma Panacis Majoris. Chinese Journal of Traditional Chinese Medicine. 35:912–914. 2010.(In Chinese).
17	Sun Y, Liu WZ, Liu T, Feng X, Yang N and Zhou HF: Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 35:600–604. 2015. View Article : Google Scholar : PubMed/NCBI
18	Wagner EF and Nebreda ÁR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI
19	Pagès PB, Le Pimpec-Barthes F and Bernard A: Surgery for pulmonary metastases from colorectal cancer: Predictive factors for survival. Rev Mal Respir. 33:838–852. 2016.(In French). View Article : Google Scholar
20	Zhao M, Chen Q, Xu W, Wang H, Che Y, Wu M, Wang L, Lijuan C and Hao H: Total ginsenosides extract induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress. J Ethnopharmacol. 243:1120932019. View Article : Google Scholar : PubMed/NCBI
21	Huang Y, Huang H, Han Z, Li W, Mai Z and Yuan R: Ginsenoside Rh2 inhibits angiogenesis in prostate cancer by targeting CNNM1. J Nanosci Nanotechnol. 19:1942–1950. 2019. View Article : Google Scholar : PubMed/NCBI
22	Jeong D, Ham J, Park S, Kim HW, Kim H, Ji HW and Kim SJ: Ginsenoside Rh2 suppresses breast cancer cell proliferation by epigenetically regulating the long noncoding RNA C3orf67-AS1. Am J Chin Med. 47:1643–1658. 2019. View Article : Google Scholar : PubMed/NCBI
23	Tang YC, Zhang Y, Zhou J, Zhi Q, Wu MY, Gong FR, Shen M, Liu L, Tao M, Shen B, et al: Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int J Oncol. 52:127–138. 2018.PubMed/NCBI
24	Nakhjavani M, Hardingham JE, Palethorpe HM, Tomita Y, Smith E, Price TJ and Townsend AR: Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer. Medicines (Basel). 6(17): 62019
25	Kim DG, Jung KH, Lee DG, Yoon JH, Choi KS, Kwon SW, Shen HM, Morgan MJ, Hong SS and Kim YS: 20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin. Oncotarget. 5:4438–4451. 2014. View Article : Google Scholar : PubMed/NCBI
26	Zhang Q, Kang X and Zhao W: Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Biophys Res Commun. 342:824–828. 2006. View Article : Google Scholar : PubMed/NCBI
27	Coffman JA: Cell cycle development. Dev Cell. 6:321–327. 2004. View Article : Google Scholar : PubMed/NCBI
28	Park M-T and Lee S-J: Cell cycle and cancer. J Biochem Mol Biol. 36:60–65. 2003.PubMed/NCBI
29	Schafer KA: The cell cycle: A review. Vet Pathol. 35:461–478. 1998. View Article : Google Scholar : PubMed/NCBI
30	Kaczanowski S: Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol. 13:32016. View Article : Google Scholar : PubMed/NCBI
31	Wong RS: Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 30:872011. View Article : Google Scholar : PubMed/NCBI
32	Arumugam A and Razis AF: Apoptosis as a mechanism of the cancer chemopreventive activity of glucosinolates: A Review. Asian Pac J Cancer Prev. 19:1439–1448. 2018.PubMed/NCBI
33	Pistritto G, Trisciuoglio D, Ceci C, Garufi A and D'Orazi G: Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 8:603–619. 2016. View Article : Google Scholar : PubMed/NCBI
34	Liu T, Wu Z, He Y, Xiao Y and Xia C: Single and dual target inhibitors based on Bcl-2: Promising anti-tumor agents for cancer therapy. Eur J Med Chem. 201:1124462020. View Article : Google Scholar : PubMed/NCBI
35	Kalpage HA, Wan J, Morse PT, Zurek MP, Turner AA, Khobeir A, Yazdi N, Hakim L, Liu J, Vaishnav A, et al: Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis. Int J Biochem Cell Biol. 121:1057042020. View Article : Google Scholar : PubMed/NCBI
36	Sun J and Nan G: The mitogen-activated protein kinase (MAPK) signaling pathway as a discovery target in stroke. J Mol Neurosci. 59:90–98. 2016. View Article : Google Scholar : PubMed/NCBI
37	Raman M, Chen W and Cobb MH: Differential regulation and properties of MAPKs. Oncogene. 26:3100–3112. 2007. View Article : Google Scholar : PubMed/NCBI
38	Fang JY and Richardson BC: The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6:322–327. 2005. View Article : Google Scholar : PubMed/NCBI
39	Berlowska J, Dudkiewicz M, Kregiel D, Czyzowska A and Witonska I: Cell lysis induced by membrane-damaging detergent saponins from Quillaja saponaria. Enzyme Microb Technol. 75-76:44–48. 2015. View Article : Google Scholar : PubMed/NCBI
40	Rao AV and Sung MK: Saponins as anticarcinogens. J Nutr. 125 (Suppl 3):717S–724S. 1995.PubMed/NCBI