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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Ginsenoside Rb1 Inhibits the Proliferation of Lung Cancer Cells by Inducing the Mitochondrial-mediated Apoptosis Pathway

Author(s): Lin Feng, Xinze Liu, Kaijing Sun, Ying Sun, Wei Wu, Changbao Chen, Xin Jin* and Xilin Wan*

Volume 24, Issue 12, 2024

Published on: 07 March, 2024

Page: [928 - 941] Pages: 14

DOI: 10.2174/0118715206299212240304142047

Price: $65

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Abstract

Background: Lung cancer is one of the more common malignant tumors posing a great threat to human life, and it is very urgent to find safe and effective therapeutic drugs. The antitumor effect of ginsenosides has been reported to be a treatment with a strong effect and a high safety profile.

Objective: This paper aimed to investigate the inhibitory effect of ginsenoside Rb1 on 95D and NCI-H460 lung cancer cells and its pathway to promote apoptosis.

Methods: We performed the CCK-8 assay, fluorescence staining assay, flow cytometry, scratch healing assay, and Transwell assay to detect the effects of different concentrations of ginsenoside Rb1 on the antitumor activity of 95D and NCI-H460 cells and Western Blot detected the mechanism of antitumor effect.

Results: Ginsenoside Rb1 treatment significantly increased the inhibition and apoptosis rates of 95D and NCIH460 cells and inhibited the cell cycle transition from S phase to G2/M. Rb1 induces apoptosis by altering the levels of P53, Bax, Cyto-c, Caspase-8, Caspase-3, Cleaved Caspase-3, Bcl-2, MMP-2, and MMP-9 proteins and activating the external apoptotic pathway.

Conclusion: Ginsenoside Rb1 inhibits proliferation and migration and induces apoptosis of 95D and NCI-H460 lung cancer cells by regulating the mitochondrial apoptotic pathway to achieve antitumor activity.

Keywords: Ginsenoside Rb1, lung cancer, 95D, NCI-H460, apoptosis, mechanism.

Graphical Abstract
[1]
Liu, W.K.; Xu, S.X.; Che, C.T. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci., 2000, 67(11), 1297-1306.
[http://dx.doi.org/10.1016/S0024-3205(00)00720-7] [PMID: 10972198]
[2]
Guo, X.Y.; Lu, M.; Chen, X.Q.; He, F.D.; Li, A. Correlation study of biological characteristics of non-small cell lung cancer A549 cells after transfecting plasmid by microbubble ultrasound contrast agent. Asian Pac. J. Trop. Med., 2016, 9(6), 582-586.
[http://dx.doi.org/10.1016/j.apjtm.2016.04.007] [PMID: 27262071]
[3]
Duan, Z.; Wei, B.; Deng, J.; Mi, Y.; Dong, Y.; Zhu, C.; Fu, R.; Qu, L.; Fan, D. The anti-tumor effect of ginsenoside Rh4 in MCF-7 breast cancer cells in vitro and in vivo. Biochem. Biophys. Res. Commun., 2018, 499(3), 482-487.
[http://dx.doi.org/10.1016/j.bbrc.2018.03.174] [PMID: 29596831]
[4]
de Groot, P.; Munden, R.F. Lung cancer epidemiology, risk factors, and prevention. Radiol. Clin. North Am., 2012, 50(5), 863-876.
[http://dx.doi.org/10.1016/j.rcl.2012.06.006] [PMID: 22974775]
[5]
An, Q.; Han, C.; Zhou, Y.; Li, F.; Li, D.; Zhang, X.; Yu, Z.; Duan, Z.; Kan, Q. Matrine induces cell cycle arrest and apoptosis with recovery of the expression of miR-126 in the A549 non-small cell lung cancer cell line. Mol. Med. Rep., 2016, 14(5), 4042-4048.
[http://dx.doi.org/10.3892/mmr.2016.5753] [PMID: 27665734]
[6]
Hong, S.Y.; Cho, J.Y.; Seo, D.W. Ginsenoside Rp1 inhibits proliferation and migration of human lung cancer cells. Biomol. Ther., 2011, 19(4), 411-418.
[http://dx.doi.org/10.4062/biomolther.2011.19.4.411]
[7]
An, I.S.; An, S.; Kwon, K.J.; Kim, Y.J.; Bae, S. Ginsenoside Rh2 mediates changes in the microRNA expression profile of human non-small cell lung cancer A549 cells. Oncol. Rep., 2013, 29(2), 523-528.
[http://dx.doi.org/10.3892/or.2012.2136] [PMID: 23152132]
[8]
Liu, D.; Liu, T.; Teng, Y.; Chen, W.; Zhao, L.; Li, X. Ginsenoside Rb1 inhibits hypoxia induced epithelial-mesenchymal transition in ovarian cancer cells by regulating microRNA-25. Exp. Ther. Med., 2017, 14, 2895-2902.
[http://dx.doi.org/10.3892/etm.2017.4889]
[9]
Yang, Z.; Wu, X.; Shen, J.; Gudamu, A.; Ma, Y.; Zhang, Z.; Hou, M. Ginsenoside Rh1 regulates gastric cancer cell biological behaviours and transplanted tumour growth in nude mice via the TGF ‐β/Smad pathway. Clin. Exp. Pharmacol. Physiol., 2022, 49(12), 1270-1280.
[http://dx.doi.org/10.1111/1440-1681.13708] [PMID: 36054718]
[10]
Jin, Y.; Huynh, D.T.N.; Myung, C.S.; Heo, K.S. Ginsenoside Rh1 prevents migration and invasion through mitochondrial ROS-mediated inhibition of STAT3/NF-κB signaling in MDA-MB-231 cells. Int. J. Mol. Sci., 2021, 22(19), 10458.
[http://dx.doi.org/10.3390/ijms221910458] [PMID: 34638797]
[11]
Li, H.; Huang, N.; Zhu, W.; Wu, J.; Yang, X.; Teng, W.; Tian, J.; Fang, Z.; Luo, Y.; Chen, M.; Li, Y. Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2. BMC Cancer, 2018, 18(1), 579.
[http://dx.doi.org/10.1186/s12885-018-4299-4] [PMID: 29783929]
[12]
Cong, Z.; Zhao, Q.; Yang, B.; Cong, D.; Zhou, Y.; Lei, X.; Zhang, X. Ginsenoside Rh3 inhibits proliferation and induces apoptosis of colorectal cancer cells. Pharmacology, 2020, 105(5-6), 329-338.
[http://dx.doi.org/10.1159/000503821] [PMID: 31671429]
[13]
Jeon, H.; Jin, Y.; Myung, C.S.; Heo, K.S. Ginsenoside-Rg2 exerts anti-cancer effects through ROS-mediated AMPK activation associated mitochondrial damage and oxidation in MCF-7 cells. Arch. Pharm. Res., 2021, 44(7), 702-712.
[http://dx.doi.org/10.1007/s12272-021-01345-3] [PMID: 34302638]
[14]
Li, J.; Yang, B. Ginsenoside Rg3 enhances the radiosensitivity of lung cancer A549 and H1299 cells via the PI3K/AKT signaling pathway. In Vitro Cell. Dev. Biol. Anim., 2023, 59(1), 19-30.
[http://dx.doi.org/10.1007/s11626-023-00749-3] [PMID: 36790693]
[15]
Song, J.H.; Eum, D.Y.; Park, S.Y.; Jin, Y.H.; Shim, J.W.; Park, S.J.; Kim, M.Y.; Park, S.J.; Heo, K.; Choi, Y.J. Inhibitory effect of ginsenoside Rg3 on cancer stemness and mesenchymal transition in breast cancer via regulation of myeloid-derived suppressor cells. PLoS One, 2020, 15(10), e0240533.
[http://dx.doi.org/10.1371/journal.pone.0240533] [PMID: 33091036]
[16]
Tang, Y.C.; Zhang, Y.; Zhou, J.; Zhi, Q.; Wu, M.Y.; Gong, F.R.; Shen, M.; Liu, L.; Tao, M.; Shen, B.; Gu, D.M.; Yu, J.; Xu, M.D.; Gao, Y.; Li, W. Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int. J. Oncol., 2017, 52(1), 127-138.
[http://dx.doi.org/10.3892/ijo.2017.4183] [PMID: 29115601]
[17]
Liang, L.D.; He, T.; Du, T.W.; Fan, Y.G.; Chen, D.S.; Wang, Y. Ginsenoside-Rg5 induces apoptosis and DNA damage in human cervical cancer cells. Mol. Med. Rep., 2015, 11(2), 940-946.
[http://dx.doi.org/10.3892/mmr.2014.2821] [PMID: 25355274]
[18]
Zhao, X.Y.; He, Z.Y.; Zai, S.F. Effects of ginsenoside Rg5 on cell cycle and invasion of gastric cancer. Chung Kuo Ying Yung Sheng Li Hsueh Tsa Chih, 2020, 36(1), 51-54.
[http://dx.doi.org/10.12047/j.cjap.5891.2020.011] [PMID: 32476373]
[19]
Lin, Z.; Xie, R.; Zhong, C.; Huang, J.; Shi, P.; Yao, H. Recent progress (2015–2020) in the investigation of the pharmacological effects and mechanisms of ginsenoside Rb1, a main active ingredient in Panax ginseng Meyer. J. Ginseng Res., 2022, 46(1), 39-53.
[http://dx.doi.org/10.1016/j.jgr.2021.07.008] [PMID: 35058726]
[20]
Lu, S.; Zhang, Y.; Li, H.; Zhang, J.; Ci, Y.; Han, M. Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-α and IL-6 in a cancer cachexia mouse model. BMC Complement. Med. Ther., 2020, 20(1), 11.
[http://dx.doi.org/10.1186/s12906-019-2797-9] [PMID: 32020864]
[21]
Lu, L.; Ao, H.; Fu, J.; Li, M.; Guo, Y.; Guo, Y.; Han, M.; Shi, R.; Wang, X. Ginsenoside Rb1 stabilized and paclitaxel/protopanaxadiol co-loaded nanoparticles for synergistic treatment of breast tumor. Biomed. Pharmacother., 2023, 163, 114870.
[http://dx.doi.org/10.1016/j.biopha.2023.114870] [PMID: 37187019]
[22]
Chen, C.; Lv, Q.; Li, Y.; Jin, Y.H. The anti-tumor effect and underlying apoptotic mechanism of ginsenoside Rk1 and Rg5 in human liver cancer cells. Molecules, 2021, 26(13), 3926.
[http://dx.doi.org/10.3390/molecules26133926] [PMID: 34199025]
[23]
Zhang, G.; He, L.; Chen, J.; Xu, B.; Mao, Z. Ginsenoside Rh2 activates α catenin phosphorylation to inhibit lung cancer cell proliferation and invasion. Exp. Ther. Med., 2020, 19(4), 2913-2922.
[http://dx.doi.org/10.3892/etm.2020.8543] [PMID: 32256776]
[24]
Chen, P.; Li, X.; Yu, X.; Yang, M. Ginsenoside Rg1 suppresses non-small-cell lung cancer via MicroRNA-126-PI3K-AKT-mTOR pathway. Evid. Based Complement. Alternat. Med., 2022, 2022, 1-12.
[http://dx.doi.org/10.1155/2022/1244836] [PMID: 35815288]
[25]
Tian, L.; Shen, D.; Li, X.; Shan, X.; Wang, X.; Yan, Q.; Liu, J. Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4. Oncotarget, 2016, 7(2), 1619-1632.
[http://dx.doi.org/10.18632/oncotarget.6451] [PMID: 26636541]
[26]
Liu, T.; Zuo, L.; Guo, D.; Chai, X.; Xu, J.; Cui, Z.; Wang, Z.; Hou, C. Ginsenoside Rg3 regulates DNA damage in non-small cell lung cancer cells by activating VRK1/P53BP1 pathway. Biomed. Pharmacother., 2019, 120, 109483.
[http://dx.doi.org/10.1016/j.biopha.2019.109483] [PMID: 31629252]
[27]
Zanotelli, M.R.; Zhang, J.; Reinhart-King, C.A. Mechanoresponsive metabolism in cancer cell migration and metastasis. Cell Metab., 2021, 33(7), 1307-1321.
[http://dx.doi.org/10.1016/j.cmet.2021.04.002] [PMID: 33915111]
[28]
Li, J.; Guo, Y.; Duan, L.; Hu, X.; Zhang, X.; Hu, J.; Huang, L.; He, R.; Hu, Z.; Luo, W.; Tan, T.; Huang, R.; Liao, D.; Zhu, Y.S.; Luo, D.X. AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling. Oncotarget, 2017, 8(20), 33694-33703.
[http://dx.doi.org/10.18632/oncotarget.16624] [PMID: 28402270]
[29]
Tungsukruthai, S.; Sritularak, B.; Chanvorachote, P. Cycloartobiloxanthone ιnhibits migration and ιnvasion of lung cancer cells. Anticancer Res., 2017, 37(11), 6311-6319.
[http://dx.doi.org/10.21873/anticanres.12082] [PMID: 29061814]
[30]
Jiang, J.; Tian, S.; Yu, C.; Chen, M.; Sun, C. TRIM37 promoted the growth and migration of the pancreatic cancer cells. Tumour Biol., 2016, 37(2), 2629-2634.
[http://dx.doi.org/10.1007/s13277-015-4078-7] [PMID: 26395261]
[31]
Dong, K.; Su, W.; Lv, Y. Long non-coding RNA TDRG1 facilitates cell proliferation, migration and invasion in breast cancer via targeting miR-214-5p/CLIC4 axis. Cancer Biol. Ther., 2021, 22(3), 248-256.
[http://dx.doi.org/10.1080/15384047.2020.1863120] [PMID: 33822672]
[32]
Chang, L.; Wang, D.; Kan, S.; Hao, M.; Liu, H.; Yang, Z.; Xia, Q.; Liu, W. Ginsenoside Rd inhibits migration and invasion of tongue cancer cells through H19/miR-675-5p/CDH1 axis. J. Appl. Oral Sci., 2022, 30, e20220144.
[http://dx.doi.org/10.1590/1678-7757-2022-0144] [PMID: 36074434]
[33]
Song, L.; Yang, F.; Wang, Z.; Yang, L.; Zhou, Y. Ginsenoside Rg5 inhibits cancer cell migration by inhibiting the nuclear factor κB and erythropoietin producing hepatocellular receptor A2 signaling pathways. Oncol. Lett., 2021, 21(6), 452.
[http://dx.doi.org/10.3892/ol.2021.12713] [PMID: 33907562]
[34]
Lee, Y.C.; Wong, W.T.; Li, L.H.; Chu, L.J.; Menon, M.P.; Ho, C.L.; Chernikov, O.V.; Lee, S.L.; Hua, K.F. Ginsenoside M1 induces apoptosis and inhibits the migration of human oral cancer cells. Int. J. Mol. Sci., 2020, 21(24), 9704.
[http://dx.doi.org/10.3390/ijms21249704] [PMID: 33352689]
[35]
Sun, M.Y.; Song, Y.N.; Zhang, M.; Zhang, C.Y.; Zhang, L.J.; Zhang, H. Ginsenoside Rg3 inhibits the migration and invasion of liver cancer cells by increasing the protein expression of ARHGAP9. Oncol. Lett., 2018, 17(1), 965-973.
[http://dx.doi.org/10.3892/ol.2018.9701] [PMID: 30655855]
[36]
Lyu, X.; Xu, X.; Song, A.; Guo, J.; Zhang, Y.; Zhang, Y. Ginsenoside Rh1 inhibits colorectal cancer cell migration and invasion in vitro and tumor growth in vivo. Oncol. Lett., 2019, 18(4), 4160-4166.
[http://dx.doi.org/10.3892/ol.2019.10742] [PMID: 31579419]
[37]
Wei, W.; Guo, Q.; Guo, C.; Cui, X.; Ma, X.; Shen, X.; Luo, Y. Ginsenoside Rh2 suppresses metastasis and growth of colon cancer via miR-491. J. Oncol., 2021, 2021, 1-7.
[http://dx.doi.org/10.1155/2021/6815713] [PMID: 34603449]
[38]
Liu, Y.; Fan, D. Ginsenoside Rg5 induces apoptosis and autophagy via the inhibition of the PI3K/Akt pathway against breast cancer in a mouse model. Food Funct., 2018, 9(11), 5513-5527.
[http://dx.doi.org/10.1039/C8FO01122B] [PMID: 30207362]
[39]
Liu, Y.; Fan, D. Ginsenoside Rg5 induces G2/M phase arrest, apoptosis and autophagy via regulating ROS-mediated MAPK pathways against human gastric cancer. Biochem. Pharmacol., 2019, 168, 285-304.
[http://dx.doi.org/10.1016/j.bcp.2019.07.008] [PMID: 31301277]
[40]
Yao, C.J.; Chow, J.M.; Chuang, S.E.; Chang, C.L.; Yan, M.D.; Lee, H.L.; Lai, I.C.; Lin, P.C.; Lai, G.M. Induction of Forkhead Class box O3a and apoptosis by a standardized ginsenoside formulation, KG-135, is potentiated by autophagy blockade in A549 human lung cancer cells. J. Ginseng Res., 2017, 41(3), 247-256.
[http://dx.doi.org/10.1016/j.jgr.2016.04.003] [PMID: 28701864]
[41]
Kim, J.S.; Joo, E.J.; Chun, J.; Ha, Y.W.; Lee, J.H.; Han, Y.; Kim, Y.S. Induction of apoptosis by ginsenoside Rk1 in SK-MEL-2-human melanoma. Arch. Pharm. Res., 2012, 35(4), 717-722.
[http://dx.doi.org/10.1007/s12272-012-0416-0] [PMID: 22553065]
[42]
Shan, X.; Tian, L.L.; Zhang, Y.M.; Wang, X.Q.; Yan, Q.; Liu, J.W. Ginsenoside Rg3 suppresses FUT4 expression through inhibiting NF-κB/p65 signaling pathway to promote melanoma cell death. Int. J. Oncol., 2015, 47(2), 701-709.
[http://dx.doi.org/10.3892/ijo.2015.3057] [PMID: 26094873]
[43]
Guo, X.X.; Li, Y.; Sun, C.; Jiang, D.; Lin, Y.J.; Jin, F.X.; Lee, S.K.; Jin, Y.H. p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells. Protein Cell, 2014, 5(3), 224-234.
[http://dx.doi.org/10.1007/s13238-014-0027-2] [PMID: 24622841]
[44]
Zhu, G.Y.; Li, Y.W.; Tse, A.K.W.; Hau, D.K.P.; Leung, C.H.; Yu, Z.L.; Fong, W.F. 20(S)-Protopanaxadiol, a metabolite of ginsenosides, induced cell apoptosis through endoplasmic reticulum stress in human hepatocarcinoma HepG2 cells. Eur. J. Pharmacol., 2011, 668(1-2), 88-98.
[http://dx.doi.org/10.1016/j.ejphar.2011.06.008] [PMID: 21703260]
[45]
Wang, L.; Zhang, Q.Q.; Xu, Y.Y.; Zhang, R.; Zhao, Q.; Zhang, Y.Q.; Huang, X.H.; Jiang, B.; Ni, M. Ginsenoside Rb1 suppresses AOM/DSS-induced colon carcinogenesis. Anticancer. Agents Med. Chem., 2023, 23(9), 1067-1073.
[http://dx.doi.org/10.2174/1871520623666230119092735] [PMID: 36655530]
[46]
Zhang, J.; Wang, J.; Wu, X.; Wei, Y. Ginsenoside Rb1 inhibits proliferation and promotes apoptosis by regulating HMGB1 in uterine fibroid cells. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 2967-2971.
[http://dx.doi.org/10.1080/21691401.2019.1643732] [PMID: 31313594]
[47]
Liu, X.Z.; Jin, X.; Wu, X.M. Comparative study on the antitumour activity of 20(R)-ginsenoside Rh2 and 20(S)-ginsenoside Rh2 from Panax ginseng against non-small cell lung cancer in vitro. Pharmacogn. Mag., 2022, 18(80)
[http://dx.doi.org/10.4103/pm.pm_583_21]
[48]
Wang, Y.; Ye, X.; Ma, Z.; Liang, Q.; Lu, B.; Tan, H.; Xiao, C.; Zhang, B.; Gao, Y. Induction of cytochrome P450 1A1 expression by ginsenoside Rg1 and Rb1 in HepG2 cells. Eur. J. Pharmacol., 2008, 601(1-3), 73-78.
[http://dx.doi.org/10.1016/j.ejphar.2008.10.057] [PMID: 19022240]
[49]
Lee, Y.J.; Jin, Y.R.; Lim, W.C.; Park, W.K.; Cho, J.Y.; Jang, S.; Lee, S.K. Ginsenoside-Rb1 acts as a weak phytoestrogen in MCF-7 human breast cancer cells. Arch. Pharm. Res., 2003, 26(1), 58-63.
[http://dx.doi.org/10.1007/BF03179933] [PMID: 12568360]
[50]
Liang, Y.Y.; Wang, B.; Qian, D.M.; Li, L.; Wang, Z.H.; Hu, M.; Song, X.X. Inhibitory effects of Ginsenoside Rb1 on apoptosis caused by HSV-1 in human glioma cells. Virol. Sin., 2012, 27(1), 19-25.
[http://dx.doi.org/10.1007/s12250-012-3220-6] [PMID: 22270803]
[51]
Li, Y.; He, F.; Zhang, Y.; Pan, Z. Apatinib and Ginsenoside-Rb1 synergetically control the growth of hypopharyngeal carcinoma cells. Dis. Markers, 2022, 2022, 1-14.
[http://dx.doi.org/10.1155/2022/3833489] [PMID: 35069931]

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